Staphylococcal antigens

ABSTRACT

The present invention provides novel sequences encoding Staphylococcus pseudintermedius proteins/nucleic acids potentially useful in the treatment and/or prevention of canine disorders. In particular, the various protein and/or nucleic acid sequences described herein may find application as vaccines for use in treating and/or preventing a variety of canine diseases and/or conditions caused or contributed to by Staphylococcus pseudintermedius.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.13/446,958, filed Apr. 13, 2012, which is a continuation-in-part ofPCT/GB2010/001916, filed Oct. 15, 2010, which claims the benefit under35 U.S.C. § 119(e) to U.S. Provisional Application No. 61/252,026, filedOct. 15, 2009, each of which are hereby incorporated by reference intheir entirety.

FIELD OF THE INVENTION

The present invention provides novel staphylococcal cell wall associatedproteins, genes encoding the same and vaccines for use intreating/preventing Staphylococcal infections.

BACKGROUND OF THE INVENTION

Skin diseases are a major cause of morbidity in dogs and an importantanimal welfare issue (Hill et al, 2006). In particular, superficialbacterial folliculitis (pyoderma) caused by Staphylococcuspseudintermedius (formerly known as Staphylococcus intermedius) is oneof the most common diseases seen in small animal veterinary practice,worldwide (Hill et al, 2006). Superficial pyoderma is characterized bythe formation of follicular pustules and is often associated withpruritus, alopecia, erythema and swelling. This may develop into deeppyoderma which typically includes pain, crusting, odor, and exudation ofblood and pus. The disease often occurs as a secondary infection in dogswith atopic dermatitis (AD) resulting from a type I hypersensitivityreaction (IgE antibody-associated) to environmental allergens (Hill etal, 2006). Treatment of canine pyoderma is often difficult withoutresorting to aggressive, medium-term administration of systemicantibacterial agents to prevent relapse of infection, and such therapypredisposes to the development of bacterial resistance that may betransferred to bacteria infecting humans (Guardabassi et al, 2004).Worringly, methicillin-resistant S. pseudintermedius has recentlyemerged as a major problem in veterinary clinics worldwide (Bannoehr etal, 2007). Although rare, several episodes of life-threateninginfections of humans by S. pseudintermedius have been reported with thetypical route of transmission being through dog bite wounds (Bannoehr etal, 2007). Previously, crude vaccine preparations based onStaphylococcus aureus phage lysate or S. pseudintermedius autogenousbacterin have shown promise as adjunctive therapies for treatment ofpyoderma (Curtis et al, 2006), and a rationally-designed effectivevaccine would be a highly desireable means to reducing or eliminatingthe suffering associated with the disease.

Accordingly, the present invention aims to obviate one or more of theproblems associated with the prior art.

SUMMARY OF THE INVENTION

The present invention is based upon the identification of novel genesequences encoding proteins potentially useful in the treatment and/orprevention of canine disorders. In particular, the proteins encoded bythe genes described herein, may find application in the treatment and/orprevention of diseases caused or contributed to by the bacterialpathogen Staphylococcus pseudintermedius.

The inventors have identified a number of Staphylococcuspseudintermedius genes encoding proteins which may broadly be classed asmembers of the cell-wall anchored (CWA) family of proteins. In certainembodiments, these CWA proteins may be further grouped as surfaceproteins known as Microbial Surface Components Recognising AdhesiveMatrix Molecules (MSCRAMM). It should be understood that while a numbermicrobial organisms may be known to express MSCRAMM type proteins, theterm “MSCRAMM” describes the phenotypic function of a wide range ofdiverse surface-associated proteins of Gram-positive bacteria. As such,while MSCRAMM proteins may all possess cell-wall anchor motifs andsignal sequences for cell wall transportation, the proteins belonging tothis group may otherwise be structurally diverse. Furthermore, bacterialspecies within a particular genus, for example the genus Staphylococcus,may possess unique MSCRAMM profiles.

In view of the above, the present invention relates to a group ofsurface expressed proteins derived from Staphylococcus pseudintermediusthat may be referred to either as CWA or MSCRAMM proteins.

As such, a first aspect of this invention provides an isolated and/orsubstantially purified Staphylococcus pseudintermedius CWA or MSCRAMMnucleic acid or protein sequence comprising a nucleic acid or amino acidsequence homologous or identical to any one of the nucleic acid or aminoacid sequences provided as SEQ ID NOS: 1-38 below.

SEQ ID NO: 1 atggaaaacaaaaacttttttagtattcgtaaactatctattggtgtaggttcttgcttaatcgcgagttctttacttgtaaacacgccaagttttgctgaagaaacagataatgcgaacattaatgacgcacaacaaaacgccttttatgaaattttacatttgccaaacttaactgaagagcaacaaaatggattcatccaaagtcttaaagatgatccaagtgtgagcaacgacattttagtagaagctaagaaattaaatgacactcaagctaaacctgattacagtgaagcacaacaaaatgcattttatgaaattttacatttgtcaaacttaactgaagagcaacaaaatggattcatccaaagtcttaaagatgatccaagtgtgagcaacgacattttagtagaagctaagaagttaaatgacactcaagctaaacctgattacagtgaagcacaacaaaatgcattttatgaaattttacatttgtcaaacttaactgaagagcaacaaaatgggttcatccaaagccttaaagatgatccaagtgtaagtaaagaaattttagcagaagctaagaagttaaatgatagtcaagcacctaaagttgataaagctaaaaaaactgacaaagctgaagcgaaagcagatgataaagctaaaggtgaagaagccaaaaaatctgaagacaaaaaagatagcaaagcagataaggcaaaatcgaaaaacgctacacatgttgttaaacctggtgaaactttagataatattgctaaagatcatcatacaactgttgataaaattgctaaagataacaaaataaaagataaaaatgtgattaaactaggtcaaaaacttgttgttgataaacaaaaagcaactcaaggaaaacaagaagctgtagcgaaaaatgaagtgaaggctttacctaatactggtgaaaatgatgatatcgcattattcagcacaacagttgcgggtggcgtaagtatcgctttaggttcattattattaggaagaaacagaaaaactagctaaThe protein sequence translated from SEQ ID NO 1 is designated SEQ IDNO: 2 and is shown below:

SEQ ID NO: 2 MENKNFFSIRKLSIGVGSCLIASSLLVNTPSFAEETDNANINDAQQNAFYEILHLPNLTEEQQNGFIQSLKDDPSVSNDILVEAKKLNDTQAKPDYSEAQQNAFYEILHLSNLTEEQQNGFIQSLKDDPSVSNDILVEAKKLNDTQAKPDYSEAQQNAFYEILHLSNLTEEQQNGFIQSLKDDPSVSKEILAEAKKLNDSQAPKVDKAKKTDKAEAKADDKAKGEEAKKSEDKKDSKADKAKSKNATHVVKPGETLDNIAKDHHTTVDKIAKDNKIKDKNVIKLGQKLVVDKQKATQGKQEAVAKNEVKALPNTGENDDIALFSTTVAGGVSIALGSLLLGRNRKTS SEQ ID NO: 3atggaaaacaaaaactttttcagcattcgtaaattatcaattggggtgggttcatgtttaatcgcgagctctttacttgtgaatacaccaagtttcgcagaagaaggagataataacgcagaagcgcaacaaaacgctttctctgaggtagtaaaattacctaaccttagcgaagaacaacgtaatggtttcattcaaagccttaaagatgatccaagtacaagtcaagatgtgcttaatgaagctaaaaaattaaatgatagtcaagagggatctcaacctgctcctgattacagtgatgaacaacaaaatgcattttatgaaattttacaccttccaaacttaactgaagaacaacgcaatggctatattcaaagtcttaaagatgacccaagtgtaagcgctaatattcttgttgaagctaaaaatatgaatgttaaccaaacacctacacaacctgcgccaagtttcgatgaagcgcaacaaaatgcattctatgagattgtaaacttaccaaatcttactgaagagcaacgtaacggtttcatccaaagccttaaagacgatccaagtgtaagtaaagatatccttgttgaagctaaaaagttaaatgacagccaagcaaaacctgattacagtgaagcgcaacaaaatgcattttatgaaattttacaccttccaaacttaactgaagaacaacgtaacggtttcatccaaagccttaaagacgatccgagtgtaagtagtgatattcttgctgaagctaagaaattaaatgacagccaagcgcctaaagaagacaacaacgtaaaagacaataattcaggtgaaaacaaagctgaagacaaaggcaacaaagaaaacaaagctgaagataaaggcagcaaagaagacaaagctgaagataaaggcagcaaagaagacaaagctgaagataaaggcagcaaagaagacaaagctgaagataaaggcagcaaagaagacaaagctgaagataaaggcagcatagaagataaagctaaagacaaagacaacaaagaaggcaaagctgcagacaaaggtatggacaaagcgaaagatgcaatgcatgtcgttcaacctggtgaaacagtagaaaaaattgctaaagctaataacacaactgtagaacaaatcgctaaagataatcatttagaagataaaaacatgattttaccaggtcaaaaacttgttgttgacaaccaaaaagcaatgaaagacagccaagaagctaaagcaaaccacgaaatgaaagctttacctgaaacaggtgaagaaaacgatatggcattattcggtacatcacttacaggtggtcttagcttagcattaggtttatacatcttaggacgtggcagaaaaacaaactaaThe protein sequence translated from SEQ ID NO 3 is designated SEQ IDNO: 4 and is shown below:

SEQ ID NO: 4MENKNFFSIRKLSIGVGSCLIASSLLVNTPSFAEEGDNNAEAQQNAFSEVVKLPNLSEEQRNGFIQSLKDDPSTSQDVLNEAKKLNDSQEGSQPAPDYSDEQQNAFYEILHLPNLTEEQRNGYIQSLKDDPSVSANILVEAKNMNVNQTPTQPAPSFDEAQQNAFYEIVNLPNLTEEQRNGFIQSLKDDPSVSKDILVEAKKLNDSQAKPDYSEAQQNAFYEILHLPNLTEEQRNGFIQSLKDDPSVSSDILAEAKKLNDSQAPKEDNNVKDNNSGENKAEDKGNKENKAEDKGSKEDKAEDKGSKEDKAEDKGSKEDKAEDKGSKEDKAEDKGSIEDKAKDKDNKEGKAADKGMDKAKDAMHVVQPGETVEKIAKANNTTVEQIAKDNHLEDKNMILPGQKLVVDNQKAMKDSQEAKANHEMKALPETGEENDMALFGTSLTGGLSLALGLYILGRGRKTN SEQ ID NO: 5gtgtacaaaaatgaagaagaaaagcattcaataagaaagttatctataggagccgcatctgtcattgttgggggactcatgtatggtgttttgggaaatgatgaagctcaagcgaatgaagatgtcactgaaacaactgggagaaattcagtgacaacgcaagcttctgagcaacatttgcaagtggaagcagtacctcaagaaggcaataatgtaaatgtatcctctgtaaaagtacctacgaatacggcaacgcaagcacaagaagatgttgcaagtgtatccgatgttaaagcacatgctgatgatgcattacaagtacaagaaagtagtcatactgatggtgtttcttcagaattcaagcaggagacagcttatgcgaatcctcaaacagctgagacagttaaacctaatagtgaagcagtgcatcagtctgaatacgaggataagcaaaaacccgtatcatctagccgcaaagaagatgagactatgcttcagcagcaacaagttgaagccaaaaatgttgtgagtgcggaggaagtgtctaaagaagaaaatactcaagtgatgcaatcccctcaagacgttgaacaacatgtaggtggtaaagatatctctaatgaggttgtagtggataggagtgatatcaaaggatttaacagcgaaactactattcgacctcatcagggacaaggtggtaggttgaattatcaattaaagtttcctagcaatgtaaagccaggcgatcagtttactataaaattatctgacaatatcaatacacatggtgtttctgttgaaagaaccgcaccgagaatcatggctaaaaatactgaaggtgcgacggatgtaattgctgaaggtctagtgttggaagatggtaaaaccatcgtatatacatttaaagactatgtaaatggcaagcaaaatttgactgctgagttatcagtgagctatttcgtaagtccggaaaaagtcttgactactgggacacaaacattcacgacgatgatcggtaatcattcaacgcaatccaatattgacgtttattatgataatagtcattatgtagatggacgtatttcgcaagtgaacaaaaaagaagctaaatttcaacaaatagcatacattaaccctaatggctatttaaatggcagggggacaattgcagttaatggtgaagtggtcagtggtacgactaaagacttaatgcaacctacagtgcgtgtatatcaatataaaggacaaggtgttcctcctgaaagtattactatagaccctaatatgtgggaagaaatcagcataaacgatactatggtaagaaaatatgatggtggctatagcttgaatctggataccagcaagaatcaaaaatatgccatctattatgaaggggcatatgatgcgcaagctgacacactgttgtatagaacatatatacagtcattaaacagttactatccgttcagttaccaaaaaatgaacggtgtgaagttttacgaaaacagtgcgagtggaagcggtgagttgaaaccgaaaccacctgaacaaccaaaaccagaacctgaaattcaagctgatgtagtagatattattgaagatagccatgtgattgatataggatggaatacagcagttggagaagaaagtggagcaaaccaaggccctcaagaagaaatcacggaaaatcacgacatcgaagtcattgaggaaaacaacttggtggaaatgacagaagatacagcagttggagaagaaagtggagcaaaccaaggccctcaagaagaaatcacggaaaatcacgacatcgaagtcattgaagaaaacaacttagtggaaatgacagaagatacagcgttggaagaagaaagtggagcaaatcaaggtcctcaagaagagatcacagaaaaccacgatatcgaagtcattgaagaaaacaacttggtggaaatgacagaagatacagcgttggaagaagaaagtggagcaaatcaaggtcctcaagaagagatcacagaaaaccacgacatcgaagtcattgaagaaaataacttagtagaaatgacagaagatacagcagttggagaagaaagtggagcaaatcaaggtcctcaagaagagatcacagaaaaccacgatatcgaagtcattgaggaaaacaacttagtggaaatgacagaagatacagcagttggagaagaaagtggagcaaaccaaggtcctcaagaagaaatcacggaaaatcacgacatcgaagtcattgaagaaaacaacttggtggaaatgacagaagatacagcgttggaagaagaaagtggagcaaatcaaggtcctcaagaagagatcacagaaaaccacaacatcgaagtcattgaagaaaacaacttggtggaaatgacagaagatacagcagttggagaagaaagtggagcaaacccaggacctcaagaagaagtaacagagaatcaacctcagcaagaagaaatcatggaaaaccaagaagtcgaaaagaaaggcgatagtaacttggtagaaagtacaaaaactccaaaggccgaagaatcagttagcgttcagccaactttagaagacaaaaacacaaagaaccacgttaacacagtagtagtgaatacgaaggtatctgaagttaaagaaaaggatccccaccatacaaaagcactaccagatacggggacaacctctcgaagtcattccatgatgattcctctccttcttgttgctgggtcagtagtgttgttacgtcgaaagaaaaagcatagtaaggtgaattaaThe protein sequence translated from SEQ ID NO 5 is designatedSEQ ID NO: 6 and is shown below: SEQ ID NO: 6VYKNEEEKHSIRKLSIGAASVIVGGLMYGVLGNDEAQANEDVTETTGRNSVTTQASEQHLQVEAVPQEGNNVNVSSVKVPTNTATQAQEDVASVSDVKAHADDALQVQESSHTDGVSSEFKQETAYANPQTAETVKPNSEAVHQSEYEDKQKPVSSSRKEDETMLQQQQVEAKNVVSAEEVSKEENTQVMQSPQDVEQHVGGKDISNEVVVDRSDIKGFNSETTIRPHQGQGGRLNYQLKFPSNVKPGDQFTIKLSDNINTHGVSVERTAPRIMAKNTEGATDVIAEGLVLEDGKTIVYTFKDYVNGKQNLTAELSVSYFVSPEKVLTTGTQTFTTMIGNHSTQSNIDVYYDNSHYVDGRISQVNKKEAKFQQIAYINPNGYLNGRGTIAVNGEVVSGTTKDLMQPTVRVYQYKGQGVPPESITIDPNMWEEISINDTMVRKYDGGYSLNLDTSKNQKYAIYYEGAYDAQADTLLYRTYIQSLNSYYPFSYQKMNGVKFYENSASGSGELKPKPPEQPKPEPEIQADVVDIIEDSHVIDIGWNTAVGEESGANQGPQEEITENHDIEVIEENNLVEMTEDTAVGEESGANQGPQEEITENHDIEVIEENNLVEMTEDTALEEESGANQGPQEEITENHDIEVIEENNLVEMTEDTALEEESGANQGPQEEITENHDIEVIEENNLVEMTEDTAVGEESGANQGPQEEITENHDIEVIEENNLVEMTEDTAVGEESGANQGPQEEITENHDIEVIEENNLVEMTEDTALEEESGANQGPQEEITENHNIEVIEENNLVEMTEDTAVGEESGANPGPQEEVTENQPQQEEIMENQEVEKKGDSNLVESTKTPKAEESVSVQPTLEDKNTKNHVNTVVVNTKVSEVKEKDPHHTKALPDTGTTSRSHSMMIPLLLVAGSVVLLRRKKKHSKVN SEQ ID NO: 7atgaataaatcaagaactaaacattttaattttttatcaaaacgtcagaatcggtatgctattcgccacttttcagctggtactgtgtcagtgcttgtaggagcagctttcttgctaggtgtccatacgagtgatgcatctgctgcagaacaagatcaaacatctgaagcaaagcaaaacctctttgatgcttccgctatttttggcgctttaacagagacgaacgaaaaggtagcacaagtgacgccaacagaaaaaaatctttcatcagttgaagaaatgagagataaaggcgcaactggaaatggaccatcaataacatcactacaaactgtagaacaaaataatgcagtacaacctacagcaacacctattaatgacacagaaaattcaaccgaagcccctatgaaagaacaatcgaatgatgcacaaacgactgacgaaagtaacaatgccactcagaaaaataatactgaaccccaagcaaacaatgaaatatcagcgcgtaatgcaaaaacaacagcatatttaacaagtgaaacctttacaacagcaacgtctacaactgatatgcctacacagaaacaagaatatccatctttagaaaatccaacaaatcaatcgcaaacgaacagagcacaaccaccaacaatggaagcacccaaactggcagaaggattagacaatctattaaaaaaatcaactttcgaaagtatgtacgtgacaaaaagaaatcaatttgacaaagagacggcttctaaaacaaaagcatggccgagtgatgttgttccagaaaatcaagtagagatacttgctgatgcaattcaaaatggctatatcaaatctgtaaatgatgtgaccaataaagcacatacgttatctggacgtgcatggatgttagaccacggaacaccaacgacaatagctaatggtttaacacctgttccagagggcactaaagtttatttgcggtggatagatcaagatggtgccacttcgccaatgtatacagcaaaaacgacaagtagattaagcgctgcggatggtaatcaagtgggtccaggtgcttatgctttcgatttacgcacaggttggatagatgctaaaggaaaacaccacgtatatagagcagtaaagggtcaatattataaaatatggatcaatgattttagaactaaagacggtaatatcgctacaatgttacgtgttgcaggaggatatgttccgggaacgtacgtggattctgtgacatacaacaatatgggccaatttccattaattggtacaaatatgcaacgtacaggtatctttatgacaacgataccttcagaaaaatatttaatatcaaaacattacgtgaaagatacaaaaggtgctgcagcaaatccagccgtcacgataattgaaaataactttgtgagcggcaaagtttggatagaaacaggtgctggagattatgtgaactcagcgacaggtccaaaccacaatgcgaaagatgtcgttgcctctggatacaaagtggtcatgtcatcattaacagatcaaggtgctaaagcctacgatgcgcaagtcaatcgcttgccgaagaaagatcgagcagaagcagcacgtcaattattaataaaacatccagaatatatcgcagcaactgtagaagggataacgaatgagtgggggagatatacattgcgtttccctaaaggcacattcaacaaagaccatctttacggttacgtattggattttgatggtgaaattgtaaaaacttattcaggttttacttcaccagagttccggagaccgaattataatttgaccgttacaccgcaaacagctccctattatagacccgttcgacgtgcatgggtcaatgttaattttgcggttattgaagcaccacaatctcaaatcgaaataaaagaatttgatgcaacctctaaccctgcgcatcgtgggcaaacagcaactattgatatcataggtatgcctaaaacttcattacttacacgtgtacaatggaaagattcatcgggcagtattgttgaggatagtggtcctgtttttacggaagaagaggctgaacatatagcggaatttgtaataccgtctagcgcaaaatcaggcgaagtgtatactgtacaactcgtggtaggtaatcatatcgtagcttcggactctcttattgtacatgtcaatgaagaagcggcgacatatcatccgatatacccatcgacaacagtagaatcaggtcaaagagtaacgattccagcacctaagaatatggatggcaaacctttactagatggcacaacttttgaaaaaggtcatcacgtaccaacttgggctttagtgaatggtgatggctcgattacagtaaaacctggagaaaaagtagcagagggtgagtatgatattccagtgattgtgacatatccagatggttctaaaaacacaatctttgcacctgtgaccgttgaagaaaaacaaccaatggcatcgcaatatgagccaataacaactggagtatcgaaaccatttggaaacccagtaatgccaactgatgtaacagattcaattcaagtaccgaactatccattggaagggcaacaaccgacagtaacagtggatgatgaaagtcaattaccagatggaacaacagaaggttacaaggatatagatgtaacagtgacatacccagacggaacaaaggatcgtgtcaaagttccagtcgtaacggaacaacaattagatagtgataaatatgatccggtcgcaacaggtatcttgaaaccgtttggtactccaacaacagaggaagacgttataaaattagtggagataccgaaatatccaacagacttaacacaaccaaaagtaacagtgacggttccaaatactttaccggatgggcaaacgccaggtaaagtagacgttgatgtgacagtaacgtatccagatggttccacagatcacatttcagttccagtttggacaaacaagcatctggataaagacaaatataacccaataacgactggggtatcgaaaccatttggaatcccagtaacgccaactgatgtaacagattcaattcaagtaccgaactatccattggaagggcaacaactgacagtaacagtggatgatgaaacacaattaccagatggaacaacagaaggtcacaaggatatagatgtaacagtgacatacccagacggaacaaaggatcatatcaaagttccagtcgtaacggaaaaacaatcagataatgaaaaatatgagccaacaactaacggaatcacgaaaaagtacggtatccctacgacagaggatgaagtgatagatatagttcgaattccatattttccagtagatggcgtgcaacctattgtaacggtaaatgatcctagactattgccaaatggtcaaaaagaaggtcaaatcaatgttccagtcacagtgacgtatccggatggcacaaaagatctcatgacagttccggttattacaggtaagcaagcagaaaatgaaaaatacgatccaatcacattaggagtaactaaagattatggtgatcctacaactgcaaacgatgtgacaaagtcaatccaaataccaacatatccagcaggtggcgaacaaccaatcgcaacagcggatgatgaaagtcaattaccggatggcacagtagaaggtaaagtggatattccagtcacagtgacgtatccggatggtactcaggatcatatcactgtcccagtatttaccaatcaacaacgagataatcaaaaagccagtaaagctgtgacgaaaatacatggtatatcggtaacaggcactgatatgacagatactaagaaaaatcataactatccagcaggtggtgaacaacctaaagttactgtgaaagatgacgatcaattatcagagggtaaagtcgattcaacagtgggtgcggataatgtgacaactacagatgatttatcaagcgtaactgcggtatctcatggtcatcaaacaagtgtacaaacaacaaaagagaaccaatcagtgcatgatgaagaggtgacgatcccaacagttgcacatgtgtctacaataatgacaggtgtggtaaagggtgagcaagaagcgacggatatcgtggctagaccacatgttgaaacaactcaactcccatcaatttcagctcaagcaacagttaaaaaactaccagaaacgggtgaaaacaatgaacaatcaggtgttttattaggtggatttattgcgttcatgggtagcttacttttattcggcagacgtcgcaaaccaaagaaagat taaThe protein sequence translated from SEQ ID NO 7 is designated SEQ IDNO: 8 and is shown below:

SEQ ID NO: 8 MNKSRTKHFN FLSKRQNRYA IRHFSAGTVS VLVGAAFLLG VHTSDASAAEQDQTSEAKQN LFDASAIFGA LTETNEKVAQ VTPTEKNLSS VEEMRDKGATGNGPSITSLQ TVEQNNAVQP TATPINDTEN STEAPMKEQS NDAQTTDESNNATQKNNTEP QANNEISARN AKTTAYLTSE TFTTATSTTD MPTQKQEYPSLENPTNQSQT NRAQPPTMEA PKLAEGLDNL LKKSTFESMY VTKRNQFDKETASKTKAWPS DVVPENQVEI LADAIQNGYI KSVNDVTNKA HTLSGRAWMLDHGTPTTIAN GLTPVPEGTK VYLRWIDQDG ATSPMYTAKT TSRLSAADGNQVGPGAYAFD LRTGWIDAKG KHHVYRAVKG QYYKIWINDF RTKDGNIATMLRVAGGYVPG TYVDSVTYNN MGQFPLIGTN MQRTGIFMTT IPSEKYLISKHYVKDTKGAA ANPAVTIIEN NFVSGKVWIE TGAGDYVNSA TGPNHNAKDVVASGYKVVMS SLTDQGAKAY DAQVNRLPKK DRAEAARQLL IKHPEYIAATVEGITNEWGR YTLRFPKGTF NKDHLYGYVL DFDGEIVKTY SGFTSPEFRRPNYNLTVTPQ TAPYYRPVRR AWVNVNFAVI EAPQSQIEIK EFDATSNPAHRGQTATIDII GMPKTSLLTR VQWKDSSGSI VEDSGPVFTE EEAEHIAEFVIPSSAKSGEV YTVQLVVGNH IVASDSLIVH VNEEAATYHP IYPSTTVESGQRVTIPAPKN MDGKPLLDGT TFEKGHHVPT WALVNGDGSI TVKPGEKVAEGEYDIPVIVT YPDGSKNTIF APVTVEEKQP MASQYEPITT GVSKPFGNPVMPTDVTDSIQ VPNYPLEGQQ PTVTVDDESQ LPDGTTEGYK DIDVTVTYPDGTKDRVKVPV VTEQQLDSDK YDPVATGILK PFGTPTTEED VIKLVEIPKYPTDLTQPKVT VTVPNTLPDG QTPGKVDVDV TVTYPDGSTD HISVPVWTNKHLDKDKYNPI TTGVSKPFGI PVTPTDVTDS IQVPNYPLEG QQLTVTVDDETQLPDGTTEG HKDIDVTVTY PDGTKDHIKV PVVTEKQSDN EKYEPTTNGITKKYGIPTTE DEVIDIVRIP YFPVDGVQPI VTVNDPRLLP NGQKEGQINVPVTVTYPDGT KDLMTVPVIT GKQAENEKYD PITLGVTKDY GDPTTANDVTKSIQIPTYPA GGEQPIATAD DESQLPDGTV EGKVDIPVTV TYPDGTQDHITVPVFTNQQR DNQKASKAVT KIHGISVTGT DMTDTKKNHN YPAGGEQPKVTVKDDDQLSE GKVDSTVGAD NVTTTDDLSS VTAVSHGHQT SVQTTKENQSVHDEEVTIPT VAHVSTIMTG VVKGEQEATD IVARPHVETT QLPSISAQATVKKLPETGEN NEQSGVLLGG FIAFMGSLLL FGRRRKPKKD SEQ ID NO: 9atgtttaatcaacaaaaacaacactatggtatccggaaatatgcaatcgggacttcatcagtattattaggcatgacattatttatcacacatgacgcaactgcatctgcagctgaaaacaatacaactgcaaagacagagacaaatcaagcagcaacaatttcttctcgcacttcgccaaccgacgtcgctcaacctaatgcagacacgaatgctacaacggcgactaaagagacaacaccacaatcagattcaacagcattaccgcaagcagcagcgcaacctcaaacgggccaaacagcatcgaaagacacagtagatacaaataaaacgcaaacagcagattccacaaccgctcctcctgtgacagacgcgccaaaagctaatgacgacacaacacagccagaagctgcgactgtagccaaaaaagaagatgctcagacaccatcgactgcagaccctacaccacaagcgcaacaaccgcctcagtcaaaagcacctcaagaaacgcaacaacaatcaacagttgaagatacaacgccacaacaaaacgcatcaactgaagcacaccctaaaaatgtagataccgcttcaacaaaacaacaacaaacaacgccatcaaccgcaccgacaccttacacacaacaagcagacgaagcaatgacagatgtcacaacaaccagtgtcgacagcaacgtacagccgttagcccctgcagaagatcaacctaaaaatacgaacacagctgacaaagcaaccgttgcgacaccaccacgtgacaatgctaagactgctgatccgaacaaaaagatgacacgtgcagcaacgacacaacaagatgatgccgtcgatacattgaagtcaaaagaaatgacagcaacgatcgataaaagttttccagccgttaaatattacacgttgaaaaatggtaaaaaagtcgatgcacaactgacggatgcacgtcaaatcatcgtcaatggtgaagtcattacaccaacagtcaaatacaacaaaattgatgatcatacggctgaatatgacttaacagcacaaaatgattcacgttcgattgatgccaattttaaatttcgtttatcagttgaaggtaagaccgttgatttacaaatgacagattacacgaacaacaacacagatccacaaaacgtcattcgcaactttagctttgtaagtcaatcgctcgtatctgtaaacaatcaacagaaaaatgccaaactgcaaacatcgaaactgtctacaaatacaatgaaaagcggcgataaatcatatcatatcgatgaaaatttcaaaaacgacttcaacgactttatgatgtacggtttcgtgtcaaatgatgattacagtgcaggattgtggagtaacgcacaaattggcgtcggcattggtgaacaagacttcttacgtgtctacgcacagtctatacaaacagatatcggggtcgctgtcggtttaggctcaatgccatggtttatccaaaaagacgctgcacatccagatgcgaaaaatcaaggactactcccacatgtcaaagttgcaattgcggaagatgaaaatcaagatggtgaaattaactggcaagacggtgcaattgcttatcgtagcattatgaacaatccatatggtgccgaagaagtacctgaccttgttgggtaccgtatcgcgatgaactttggttctcaagcgcaaaacccatttttaaagacgttagatggtgtgaaaaaattctatctcaatacagatggtttagggcaatccattttattaaaaggttataacagtgaaggccacgactctggtcatttagattacgcgaatattggtcaacgtataggtggcgtgaaagactttaaaacgttacttcaaaaaggggcagattatggcgcacgtttcggtcttcatgtgaatgcatctgaaacatatccagagtctcaagcattcaatcctgccctcttacgtaaagatgcgaatggaaactatatgtatggctggaactggctcgatcaaggctttaacatcgatgcagattacgatttaatacacgggcgtaaagaacgcttcgaagcactcaaacaaattgtcggtgatgacctcgactttatttatgtcgatgtatgggggaatggacaatccggcgacaatacagcttggccatcacatcaattagccaaagaaatcaacgacttaggatggcgcgtcggtgtcgaatggggtcacggtatggaatatgactccacgttccaacattgggcagccgacttaacgtatggatcgtaccaaaataaagggattaactcagaggtagcacgcttcttacgcaaccatcaaaaagattcatgggtcggtaactatccaaaatactcaggtgcagctgacttcccattgctcggcggttatgacatgaaagattttgaaggttggcaaggtcgtaacgattactctgcttacattaaaaatattttcaatgttgatgtaccaacaaagtttttacaacattataaagtgatgcgtattgtcgatggtgagcctgttaaaatgactgccaatggtcaaacgattgactggacaccagaaatgcaagtcgatttacaaaatgaagccggtgatcaagtcactgttaaacgtaaatctaacgactatgaaaacgacactgacaactaccgctcacgtacaatcgaattgaatggtcgcacagtactcgatggcgattcataccttttaccatggaattgggatgcgaacggccaaccattaactggcgataacgaaaaattatatcactggaataaaaaaggcggttcaacgacttggacactgcctgaatcatgggatacagaccaagtcgtgctatacgaattatctgaaacgggtcgtaagtcaccacgtacagtggcagtgaaagaccatcaagtgacactcgataatattaaagcagacacaccgtatgtcgtttataaagtcgcacaaccagacaacacagatgtgaactggagcgaagacatgcacgtgaaagatgccggcttcaactcacaacaactgacaccttggacaatcgaaggcaatcgagataaagtgagcatcgaaaagtcgacaacatcaaatgaaatgctaaaaatcgatagtccaacaaaaacaacgcaattaacgcaacaattgacaggtttagtgccaggacaacgttacgctgtctatgttggcatcgataaccgcagtgatgcagcggcgcatattgcagtgacacataacggtaaaacgctcgcaagtaacgaaacaggtcaatcgatcgcgaaaaactatgtgaaagcagatgcacatagtaacaatgctgcgacgtttaaaaatggcggtagttacttccaaaacatgtacgtgtacttcgttgcgccagaagatggtaaagcagacttgacgattcaacgcgacccaggtgaaggggccacttatttcgatgatattcgtgtgttagaaaataacgcgaatctccttcaaaacggcacattcaaccaagacttcgaaaatgtaccacaagggttattcccgttcgtcgtgtcagaagttgaaggcgttgaagataatcgcgttcacttatctgaaaagcacgcaccgtatacacaacgcggatggaataataaacgtgtcgatgatgtcattgatggcaaatggtcacttaaagtaaacggtcaaacaggtaaagataaaatggtcatccaaacgattccgcaaaacttctacttcgaaccaggaaaaacgtatgaagtgtcatttgattatgaagcaggttctgatgatacgtatgcatttgcgacaggtagtggggacatttctaaaaatcgtaactttgaaaagacaccattgaaaaatacagtcgatggtggcaaagcgaaacgggtgacatttaaagtgacgggtgatgaaaatggtcaaacttggatcggtatttactcaacgaaaacacccaatgatccacgaggcgtgaaaaatggcaatcaaatcaacttcgaagggacgaaagatttcattctagacaacctttctatccgtgaaattgacgcaccgaagcctgatgccacacaagaaagcggtgatagcgcaccaatgaatgaaacagatgagcgtaacgtcaattcaaacggtacattagccgatcatagtgagacaactgatgtcaatgtcagtgcaacggcagatgatacagcagtcaaaggcgaaatgacgacaaacagaacagatgcaccaactgttacactgcctgaagcaacgatagtagatgaaggcacgtcaaatcctgtcactacaacaccaacgaatacaacacaagctatgacaaataaggctgatgagatgccacaaacgatgaacaatgttcctttaactagcatcgctaccgatatgatgcagtctcatgcggtggattccatggcagcaacactagcagctacaaatcaagtggcggcacctgtgcgtcaaacagcaggacctatgcaacatggtatggacagtgcttcaacgcaacacgcacccatacaagttgacaatgtcacagcaccaccattaccagatgaacagtttgccgaattacctaaaactggggatacgactccaaatacacgtggacctttaatggcgatgatagttggcgcagtcttaacagcattcggattcagacgccaacgtaaagaaaaatagThe protein sequence translated from SEQ ID NO 9 is designated SEQ IDNO: 10 and is shown below:

SEQ ID NO: 10MFNQQKQHYGIRKYAIGTSSVLLGMTLFITHDATASAAENNTTAKTETNQAATISSRTSPTDVAQPNADTNATTATKETTPQSDSTALPQAAAQPQTGQTASKDTVDTNKTQTADSTTAPPVTDAPKANDDTTQPEAATVAKKEDAQTPSTADPTPQAQQPPQSKAPQETQQQSTVEDTTPQQNASTEAHPKNVDTASTKQQQTTPSTAPTPYTQQADEAMTDVTTTSVDSNVQPLAPAEDQPKNTNTADKATVATPPRDNAKTADPNKKMTRAATTQQDDAVDTLKSKEMTATIDKSFPAVKYYTLKNGKKVDAQLTDARQIIVNGEVITPTVKYNKIDDHTAEYDLTAQNDSRSIDANFKFRLSVEGKTVDLQMTDYTNNNTDPQNVIRNFSFVSQSLVSVNNQQKNAKLQTSKLSTNTMKSGDKSYHIDENFKNDFNDFMMYGFVSNDDYSAGLWSNAQIGVGIGEQDFLRVYAQSIQTDIGVAVGLGSMPWFIQKDAAHPDAKNQGLLPHVKVAIAEDENQDGEINWQDGAIAYRSIMNNPYGAEEVPDLVGYRIAMNFGSQAQNPFLKTLDGVKKFYLNTDGLGQSILLKGYNSEGHDSGHLDYANIGQRIGGVKDFKTLLQKGADYGARFGLHVNASETYPESQAFNPALLRKDANGNYMYGWNWLDQGFNIDADYDLIHGRKERFEALKQIVGDDLDFIYVDVWGNGQSGDNTAWPSHQLAKEINDLGWRVGVEWGHGMEYDSTFQHWAADLTYGSYQNKGINSEVARFLRNHQKDSWVGNYPKYSGAADFPLLGGYDMKDFEGWQGRNDYSAYIKNIFNVDVPTKFLQHYKVMRIVDGEPVKMTANGQTIDWTPEMQVDLQNEAGDQVTVKRKSNDYENDTDNYRSRTIELNGRTVLDGDSYLLPWNWDANGQPLTGDNEKLYHWNKKGGSTTWTLPESWDTDQVVLYELSETGRKSPRTVAVKDHQVTLDNIKADTPYVVYKVAQPDNTDVNWSEDMHVKDAGFNSQQLTPWTIEGNRDKVSIEKSTTSNEMLKIDSPTKTTQLTQQLTGLVPGQRYAVYVGIDNRSDAAAHIAVTHNGKTLASNETGQSIAKNYVKADAHSNNAATFKNGGSYFQNMYVYFVAPEDGKADLTIQRDPGEGATYFDDIRVLENNANLLQNGTFNQDFENVPQGLFPFVVSEVEGVEDNRVHLSEKHAPYTQRGWNNKRVDDVIDGKWSLKVNGQTGKDKMVIQTIPQNFYFEPGKTYEVSFDYEAGSDDTYAFATGSGDISKNRNFEKTPLKNTVDGGKAKRVTFKVTGDENGQTWIGIYSTKTPNDPRGVKNGNQINFEGTKDFILDNLSIREIDAPKPDATQESGDSAPMNETDERNVNSNGTLADHSETTDVNVSATADDTAVKGEMTTNRTDAPTVTLPEATIVDEGTSNPVTTTPTNTTQAMTNKADEMPQTMNNVPLTSIATDMMQSHAVDSMAATLAATNQVAAPVRQTAGPMQHGMDSASTQHAPIQVDNVTAPPLPDEQFAELPKTGDTTPNTRGPLMAMIVGAVLTAFGFRRQRKEK SEQ ID NO: 11atgacaagaaaatttagggaatttaagaaaagtttaagtgaagaaaaagcaagagtgaaactttacaagtcaggtaaaaactgggttaaagctggaattaaagaatttcagttattaaaagcattaggcttatcttttttaagccatgacattgtaaaggatgaaaatggagaagtaacgacacaatttggggaacagttgaagaaaaatgcattaagaacaactgcttttgcgggtggaatgttcacagttaatatgttgcatgaccaacaagcatttgcggcgtcggatgcacctataacttctgaactggcaaccaaaagtcaaactattggcgatcaaacatcaattgttattgaaaagtctacatcgtcagatcaatcaacgaacccaataacagaaagtgaaagtaaacacgattctgaaagtatctcattatctgagcatcaaacatcagagtcaacaagtctttcaacgtcaacttccaaatcaatatcaacttcagtagaggaatcagaatcaacatcaaaagattctcatactaaaactcaagatagtcaatcagatagtcatcagtcaacaagtcaagaggtaaatggctcttccaaccacgagcaatcaacaccacacactgcacaaagtcttacgagcctatctattgagagccaaacgtcgacttcaaatacatcattgaaggaaactaaagaaggggaattgtcaaaaaacctttcgaagttatctcaaaatcaaaacatcaaacttcatgaagaacatacgatgcgttcagcagatttgagctcaggttatacaggatttagagcggcttactatgtaccaagatcaagaacaacaccaacgacaaaagtctacacagggcaaggaagcttcagaggtagaggtagaattaaatataatattttctacaaagttgtcgttacaagtaatggcaaagaaatgaagatccgctatacattgagtcaagatgatccaaacacgtctaatgttgaaaaacctaggtgggcaggacagaaacgatttggtattcataatacttgggatgaaggtcctggtcgcgggcaattaaagttagggtcggcattcggcaaaccaacagttatacaaggagaaactagaccgaattatggtagctgggttggcacacctataacgaaatatgtttcaggcgatcgtacaaatggtttttactggcaagctgctgtacttgcaccgagacatggagagaagggagaaggaatcacagcagaaattacagttcctattgttaacccttctggaagatttaattgggaattccatcctgtcggtcaacaggacggagttggtggcaaaactgactactttgaaaatgtatggattcgagactatgacccatattacaaatatattcaaactaaggaaggcagagcctcagtttcgcactctatttctcaggtgaaagcaagtgaatcgagatcgacatcgctcatacaatcggagtctattagaagatcacagtccatatctgagagtgaatctattgtagccgcaagtcattcggcaagtgtagcaaaatcgcaatccatctcgagaagtcaatctgtggcgaaatcacaatcgatctcaagaagtcagtcgatcgcacacagccgatcagcaagtgtggcaaaatcgcaatccatctcaagaagtcagtcgatcgcacacagccgatcagcaagtgtggcaaaatcacaatcgatttcaagaagtcagtcgatcgcacacagccgatcagcaagtgtggcgaaatctcaatcgatttcaagaagtcagtcaattgcgcagagccaatcagcaagtgtggcaaaatcacagtcgatttcaagaagtcagtcaattgcgcagagccaatcagcaagtgtggcgaaatcgcaatcgatttcaagaagtcagtcgattgcacatagccgatcagcaagtgtagcggaatcacagtcgatttcaagaagtcagtcgattgcgaatagccaatctgtagcagcgagtgaatcagagagtctatcaatatcattgtctaaaaagcagtcaatatcgatgagtaattctgaaagtgcagcaaaatcacactcgctttcggtgaaaaggtctaactggattaaaaagtcaaaagcggcttcagtaagaaagtcacattcactttcggtaagaaaatctaattcggcgaaaaggtcacatgctatttcggtaagaaagtcaaagtcattatcagttaaaaagtcaatttcgcagagccaatcagcaagtgtggcgaaatcgcaatcgatttcaagaagtcaatcagtagcagcgagtgagtcggcatcgctaagtaagtcgaagagcacatcgctcagtaactcagtgagtgcagagaaatcgacgtcattaagtcgttcagcaagtgtagcaaaatcgcaatcgatttcaagaagccaatcagtagtagcgagcgaatcggcatcgttaagtaagtcgaagagcacatcgctcagtaactcagtgagtgcagagaaatcgacgtcattaagtcgatcagcaagtgtagcaaaatcgcaatcgatttcaagaagccaatcggtggcagcgagcgaatcggcatcgttaagtaagtcgaagagcacatcgctcagtaactcagtgagtgcagagaaatcgacgtcattaagtcgatcagcaagtgtagcaaaatcgcaatcgatttcaagaagccaatcggtggcagcgagcgaatcggcatcgttaagtaagtcgaagagcacatcgctcagtaactcagtgagtgcagagaaatcgacgtcattaagtcgatcagcaagtgtggcaaaatcgcaatcgatttcaagaagccaatcagtagtagcgagcgaatcggcatcgttaagtaagtcgaagagcacatcgctcagtaactcagtgagtgcagagaaatcgacgtcattaagtcgatcagcaagtgtagcaaaatcgcaatcgatttcaagaagccaatcggtggcagcgagcgaatcggcatcgttaagtaagtcgaagagcacatcgctcagtaactcagtgagtgcagagaaatcgacgtcattaagtcgatcagcaagtgtggcaaaatcgcaatcgatttcaagaagccagtcagtagcagcaagtgagtcggcatcattaagtaagtcgaagagcacatctttaagcaactcagtgagtgtagagaaatcgacgtcattaagtcgatcagcaagtgtggcgaaatcgcaatcgatttcaagaagtcaatcagtagcagcgagtgagtcggcatcgctaagtaagtcgaagagcacatcgctcagtaactcagtgagtgcagagaaatcgacgtcattaagtcgttcagcaagtgtagcaaaatcgcaatcgatttcaagaagccagtcagtagcagcaagtgagtcggcatcattgagtaaatcaacaagtacgtcaacaagtgactcagatagcgcgtcaacatcaacatctgtatcagatagcgattcagcttcattgagtaagtcgactagtacatcaacaagcgattcagacagcgcgtcagcatcattgagcaagtcaacaagtacatcaacgagcgactcagatagcgcatcgacatcaacatcagtatcagatagcgactccgcatcgttgagtaaatcgacaagcacgtcaacaagtgattcagacagcacgtctacttcattgagtaagtcgacaagtacatcgacaagtgattcagatagtgcgtcaaaatcaacgtcagtatcagacagtacgtccgcatcattgagtaaatcgacaagcacgtcaacaagtgattcagatagtgcatcaaaatcaacgtcggtatcagatagcacgtcagcatcattaagaaagtcggcaagtacgtcaacgagtgactcagacagcacgtctacttcattgagtaagtcgacaagtacatcgacaagtgattcagatagtgcatcaaaatcaacatcagtatcagatagcgattcagcttcattgagtaagtcgactagtacatcaacaagcgattcagatagtgcgtcaaaatcaacgtcggtatcagatagcgactccgcatcgttgagtaagtcgacaagtacgtcaacaagcgattcagacagtgcatcaaaatcaacgtcggtatcagacagtacgtcaacatcattaagtaagtcgacaagtacatcaacaagcgattcagatagtgcgtcaacatcgacatcagtatcggacagtacgtctgcatcattgagtaagtcgacaagcacatcgacaagtgattcagatagcgcatcaacatcagtgtcagatagcgattcagcatcactaagcaagtcaacaagtacatcgacaagcgattcagacagcgtatcaacatcaacatcagtatcagatagtgattccgcgtcattaagtaagtcgacaagtacgtcaacaagcgattcagatagtgcgtcaaaatcaacatcagtatcagatagcacgtcaacatcattgagtaaatcaacaagtacatcgacaagtgactcagatagtgcgtcaacatcggtatcagacagtacgtccgcatcattgagtaaatcgacaagcacgtcaacaagtgattcagatagtgcatcaaaatcaacatcagtatcagatagcgattcagcatcattaagcaagtcgacaagtacatcgacaagtgattcagatagtgcgtcaacatcaacgtcagtgtcagatagcgattcagcttcattaagcaaatcaacaagtacgtcaacaagtgactcagatagcgcatcaacatcattaagcaagtcaacaagtacatcgacaagcgattcagacagtacgtctacatcattaagtaagtcaacaagtacatcaacaagtgattcggatagtgcgtcaaaatcaacatcagtatcagatagcgactcagcttcattaagcaagtcgacaagtacgtcaacaagtgactcagacagtgcgtcaaaatcaacatctgtgtcagatagcgactccgcatcgttgagtaagtcgacaagtacgtcaacgagcgattcggatagtgcgtcaaaatcaacatcagtatcagatagtgaatccgcgtcattaagcaagtcgacaagcacatcgacaagtgactcagatagtgcgtcaacatcgacatcggtatcagacagcacatcagtttcattaagcaagtcgacaagcacgtcaacaagcgattcagacagtacgtctacttcattaagcaagtcgacaagcacgtcaacaagtgactcagatagtgactcagcttcgttgagtaaatcgacaagcacgtcaacgagcgattcagatagcgtgtcaacatcaacatctgtgtcagatagcgattcagcttcattaagcaaatcgacaagtacatcaacaagcgattcagatagtgcgtcaacatcaacgtcggtatcagatagcggctccgcatcgttgagtaagtcgacaagtacgtcaacgagcgattcagacagtgcatcaaaatcaacgtcggtatcagatagtgattcagcatcactaagcaaatcgacaagcacgtcaacaagtgactcagacagtgcgtcaacatcgacatcggtatcagatagcacatccgcgtcgttaagcaagtcgacaagtacgtcaacaagtgattcagacagcgcatcgacatcaacatcagtatcagatagcgactccgcatcgttgagtaaatcgacaagcacgtcaacaagtgattcggacagtgcgtcaaaatcaacatcagtgtcagatagcgattcagcttcattgagtaagtcgacaagcacgtcaacaagcgaatcagacagcgcgtcaaaatcaacgtcagtgtcagatagcgattccgcatcattaagtaaatcgacaagcacgtcaacaagtgactcagatagtgcatcgacatcaacgtcagtatcagatagtgattccgcgtcattaagcaagtcgacaagtacgtcaacaagtgactcagacagtgcgtcaaaatcaacatcagtatcagatagcgattccgcatcattgagtaagtcgacaagcacgtcaacaagcgaatcagacagtgcgtcaacatcgacattagtatcggatagtacgtcggtttcattgagccaatcaacaagtgtggataaagatagtacagcgaagggatcgacagaattagtaaatgttgcatcactttcaatcagtgcgagtcaatcaagtagtttatctgcttcaacatccacatcgattgaaaagtctgagtctacatcaacaagtggctcaaattcaactaatgcgtcgttaagtagctcatcttcacttagtacatcagcaagtacttctgtaagcgaagtgacatctgtcacacattctgaaaatgatttaagtgcatctaacgatagagatacatccggatcagtaagtcaatttgcttctgaaaatacatcattaagtgattctgcatcaattagtggcgaagtttctagtagtacgtccgcgtcaacttcgaaatcatcatcactttcagcaagcgcgttacatgataagcatgtatcagaaagcacttctgcatcattaagtagtggagattcaagtcgtgcttcggcatcagtgtcaacgtcattatcagaatcagatagtgcgttaatagactctgaatcaattagcgtttccgagcacacatcaacattacaatcaggtagtcattcactatcacaacaacaatcagcagaattatcacaatcagagcaaacatcacaatcacaacgcatttcaacaagtgcgtcagtatcggctatgaaatcagaaagtgctgctaaggtatctgaatcgctatctacgtctcaatcaaaagtagatagtcaatcacaatcggtatctgaatcagcgagcaactcacgagtgtcaagagattcaaaatcaacaagcgcttcaatgcatcgatcattgtcagagtcagtatctcaaagtatgtcacttattgatcagtcagaaagtgattcaacatctatatcgatttcgacgtcaatcagtgatgaagactctatgctgtattctatgagtgattccgcatcgatcagtactaaggcatcaagtagtatgtctacttcgacaagcgaagagcatgccaacagtcattctcagtctgaatcgacagcatcggttgaagtatctcaagaaatgagtgcatcggcttcaacaagcaaatctgagtctcaatcagagtcagtatcagtaagtaacgaagaatcaaatatctcatctatgcaagagtcttttgtagagagtgcaaaagcatcgcgtagtgcatctatgagcgttgcaaaatctgaagcctctgaatcacagctattaagtgagtctaatgcttcggtaagccaatcagcaagcacaagtagtaaagcatcagcaagtacgtcagaatctatttcaacgtcactcagcgtatctgaagcaactcatggaaaaccgagaaatcattcagaaagtgcatcagcaagtcaattattagaagaaaatgagtcattaagcgattcagcatcaacaagtgttgaagattcagaaagtgcatcagcatctctgtcggtgtatcaatcacaatcagcaagtgcattgaaatcaacacatgcatcagaaaaagcttcagtgaatacaagtgcaaacgcatcgaagcgtgcatcagcatcgacatctatctctaactcgaaatctaaagtcattgcgagtgaatcgaagtcaacaagcatatcaacatatgaatcgttgtcaatatcgactagtaaagaacaatcaacgcgtgtatcagtgagtgagtcgacatcaacgtctaaagtgaagtcagaaagcgactcggcatcaacgtcgacatctgaatcaatctcaattagcgcaaatcgttcaggttacacatcgtctaaacgttcggtacaaatgagtgaagcacaatcaacgagcgattcattatcagtaatgcaatctgaaggttcagtaagtgtatcgcaatctttaagtatatcagataagacatcacagtccttatcggaatcaatatcgcattcagaaagtgactctgatagtaactcagtgtctattagtcaagagacatctgaacaacattcggtgtcagacagtgactcgatgtcaatttcggaaagcgaatctattgcatatagtcaatcagcgagtgaatcagaatcaacaagtatcgcaaaatctgatagtatttcgaactcattatctgtttcattaagtgaatcagaaagtgaagcaagcacatcagcttcagtgagtacatctgaaagtacgtctgtaaagggttctctatcaacaagtatcttgaacagtcaatcagcatctactcatcaatcaacagaagcttctcaaagtacatcaacttcaaaagttgaggaagcatcattgagtgactctgcttctgtatcagattcacaatcactttcaatgagtcatgagaaatcacaaagtgcatcgacttcaaaatctacgagtctgtcaaaaactatttctgagtcagagtctgtgagtgcatcaacatcaacaagtgaagctgtaagtacagaagcaagcgaatttgtatcagcagtagactcattgagtcaagtaacttctaacggaagcacaacgaaagaagatgcgagtacatttgtatccacagtagattcattgaaagacaaagcatcaaataatggtacaccatcagagtttgcgtcagcagtgaaatcaacacacgcatcagtgagtgtgtcagcatcagaaagtacgtcagcatcaacatcaacaagtgaagctgtaagtacagaagcaagcgaatttgtatcagcagtgaattcgttgagtgaagcgacttctaacggaagcacaacgaaagaagatgcgagtacatttgtatccacagtagattcattgaaagacaaagcatcaaataatggtacaccatcagagtttgcgtcagcagtgaaatcaacacacgcatcagtgagtgtgtcagcatcagaaagtacatcagcatcaacatcaacaagtgaagctgtaagtacagaagcaagcgaatttgtatcagcagtagactcattgagtcaagtaacttctaacggaagcacaacgaaagaagatgcaagcacatttgtatccacagtagattcattgaaagataaagcatcaaacaatggtacaccatcagaatttgaatcagttgtgaaatcagtacacggatcaatgagtgcatcagcaagtgcgtcaacatcagcatctacatcagcatctacatctacaagtgaagctgcaagtgcagaagcaagcgaattagaatcagtaaggaaatcattatccaatggagcatcaaacggtagcacagcaagagaaggtgcaagcacatttgtatcaacggtagattcattgaaagataaagcatcaaacaatggtacagcatcagaatttgaatcagttgtgaagtcagtacacggatcaacaagtgcatcagcaagtgcgtcaacgtcagcatcaacatcagcaagtgaatcagcaagtacagaagcaagtgaatttgtatcagcagtggcatcattaagcagttcagcatggaacggaagcactacaggagaaggtgcaagcacatttgtatcaacagttgattcatcgaaagattcagcgtcagacaaagcttcaccatcagaatcagaatcagttgtgaagtcagtacacggatcaacgagtacatcagcaagtgtgtcagcgtcggcaagtacatcagcatcgacatcaacaagtgaagctgtaagcacagaagcaagtgagtttgtatcagcagtgaactcattaagcagtgaagcatcgaacggcagcacaacaagagaaggtgcaagcacatttgtatcaacagtagattcattgaaagacaaagcatcaaacaatggtacagcatcagaatttgaatcagttgtgaagtcagtacacggatcaatgagtacatcagcaagtgtgtcagcatcagaaagtacgtcggcatcgacatcgacaagtgaagctgtaagtacagaagcaagcgagtcagcatcgataagtgtatcaatgtcagtgagcgcatcaacaagtgcttcaatgagcgtatcagtgtcaaacagtgtgtcagtgagtgactctatttcagtaagtgcatcaacaagtgaacctaactcggtaagcacttctatgagtagttctctttcaacatcggcatcaacgccatcagaaattacttcaagttcgtcatcaagcgattcagcgacagttcaaaaagtagtttctaaagatgaacagcacgctacaaataaagttgaaaaattacctgacacaggtcaatcaacgacacaaactggtttattgggtggagtaggtgctttacttacaggccttggtttactcaaaaaatcaagaaaacaaaaagatgaagaaacatcatca catgaataaThe protein sequence translated from SEQ ID NO 11 is designated SEQ IDNO: 12 and is shown below:

SEQ ID NO: 12 MTRKFREFKK SLSEEKARVK LYKSGKNWVK AGIKEFQLLK ALGLSFLSHDIVKDENGEVT TQFGEQLKKN ALRTTAFAGG MFTVNMLHDQ QAFAASDAPITSELATKSQT IGDQTSIVIE KSTSSDQSTN PITESESKHD SESISLSEHQTSESTSLSTS TSKSISTSVE ESESTSKDSH TKTQDSQSDS HQSTSQEVNGSSNHEQSTPH TAQSLTSLSI ESQTSTSNTS LKETKEGELS KNLSKLSQNQNIKLHEEHTM RSADLSSGYT GFRAAYYVPR SRTTPTTKVY TGQGSFRGRGRIKYNIFYKV VVTSNGKEMK IRYTLSQDDP NTSNVEKPRW AGQKRFGIHNTWDEGPGRGQ LKLGSAFGKP TVIQGETRPN YGSWVGTPIT KYVSGDRTNGFYWQAAVLAP RHGEKGEGIT AEITVPIVNP SGRFNWEFHP VGQQDGVGGKTDYFENVWIR DYDPYYKYIQ TKEGRASVSH SISQVKASES RSTSLIQSESIRRSQSISES ESIVAASHSA SVAKSQSISR SQSVAKSQSI SRSQSIAHSRSASVAKSQSI SRSQSIAHSR SASVAKSQSI SRSQSIAHSR SASVAKSQSISRSQSIAQSQ SASVAKSQSI SRSQSIAQSQ SASVAKSQSI SRSQSIAHSRSASVAESQSI SRSQSIANSQ SVAASESESL SISLSKKQSI SMSNSESAAKSHSLSVKRSN WIKKSKAASV RKSHSLSVRK SNSAKRSHAI SVRKSKSLSVKKSISQSQSA SVAKSQSISR SQSVAASESA SLSKSKSTSL SNSVSAEKSTSLSRSASVAK SQSISRSQSV VASESASLSK SKSTSLSNSV SAEKSTSLSRSASVAKSQSI SRSQSVAASE SASLSKSKST SLSNSVSAEK STSLSRSASVAKSQSISRSQ SVAASESASL SKSKSTSLSN SVSAEKSTSL SRSASVAKSQSISRSQSVVA SESASLSKSK STSLSNSVSA EKSTSLSRSA SVAKSQSISRSQSVAASESA SLSKSKSTSL SNSVSAEKST SLSRSASVAK SQSISRSQSVAASESASLSK SKSTSLSNSV SVEKSTSLSR SASVAKSQSI SRSQSVAASESASLSKSKST SLSNSVSAEK STSLSRSASV AKSQSISRSQ SVAASESASLSKSTSTSTSD SDSASTSTSV SDSDSASLSK STSTSTSDSD SASASLSKSTSTSTSDSDSA STSTSVSDSD SASLSKSTST STSDSDSTST SLSKSTSTSTSDSDSASKST SVSDSTSASL SKSTSTSTSD SDSASKSTSV SDSTSASLRKSASTSTSDSD STSTSLSKST STSTSDSDSA SKSTSVSDSD SASLSKSTSTSTSDSDSASK STSVSDSDSA SLSKSTSTST SDSDSASKST SVSDSTSTSLSKSTSTSTSD SDSASTSTSV SDSTSASLSK STSTSTSDSD SASTSVSDSDSASLSKSTST STSDSDSVST STSVSDSDSA SLSKSTSTST SDSDSASKSTSVSDSTSTSL SKSTSTSTSD SDSASTSVSD STSASLSKST STSTSDSDSASKSTSVSDSD SASLSKSTST STSDSDSAST STSVSDSDSA SLSKSTSTSTSDSDSASTSL SKSTSTSTSD SDSTSTSLSK STSTSTSDSD SASKSTSVSDSDSASLSKST STSTSDSDSA SKSTSVSDSD SASLSKSTST STSDSDSASKSTSVSDSESA SLSKSTSTST SDSDSASTST SVSDSTSVSL SKSTSTSTSDSDSTSTSLSK STSTSTSDSD SDSASLSKST STSTSDSDSV STSTSVSDSDSASLSKSTST STSDSDSAST STSVSDSGSA SLSKSTSTST SDSDSASKSTSVSDSDSASL SKSTSTSTSD SDSASTSTSV SDSTSASLSK STSTSTSDSDSASTSTSVSD SDSASLSKST STSTSDSDSA SKSTSVSDSD SASLSKSTSTSTSESDSASK STSVSDSDSA SLSKSTSTST SDSDSASTST SVSDSDSASLSKSTSTSTSD SDSASKSTSV SDSDSASLSK STSTSTSESD SASTSTLVSDSTSVSLSQST SVDKDSTAKG STELVNVASL SISASQSSSL SASTSTSIEKSESTSTSGSN STNASLSSSS SLSTSASTSV SEVTSVTHSE NDLSASNDRDTSGSVSQFAS ENTSLSDSAS ISGEVSSSTS ASTSKSSSLS ASALHDKHVSESTSASLSSG DSSRASASVS TSLSESDSAL IDSESISVSE HTSTLQSGSHSLSQQQSAEL SQSEQTSQSQ RISTSASVSA MKSESAAKVS ESLSTSQSKVDSQSQSVSES ASNSRVSRDS KSTSASMHRS LSESVSQSMS LIDQSESDSTSISISTSISD EDSMLYSMSD SASISTKASS SMSTSTSEEH ANSHSQSESTASVEVSQEMS ASASTSKSES QSESVSVSNE ESNISSMQES FVESAKASRSASMSVAKSEA SESQLLSESN ASVSQSASTS SKASASTSES ISTSLSVSEATHGKPRNHSE SASASQLLEE NESLSDSAST SVEDSESASA SLSVYQSQSASALKSTHASE KASVNTSANA SKRASASTSI SNSKSKVIAS ESKSTSISTYESLSISTSKE QSTRVSVSES TSTSKVKSES DSASTSTSES ISISANRSGYTSSKRSVQMS EAQSTSDSLS VMQSEGSVSV SQSLSISDKT SQSLSESISHSESDSDSNSV SISQETSEQH SVSDSDSMSI SESESIAYSQ SASESESTSIAKSDSISNSL SVSLSESESE ASTSASVSTS ESTSVKGSLS TSILNSQSASTHQSTEASQS TSTSKVEEAS LSDSASVSDS QSLSMSHEKS QSASTSKSTSLSKTISESES VSASTSTSEA VSTEASEFVS AVDSLSQVTS NGSTTKEDASTFVSTVDSLK DKASNNGTPS EFASAVKSTH ASVSVSASES TSASTSTSEAVSTEASEFVS AVNSLSEATS NGSTTKEDAS TFVSTVDSLK DKASNNGTPSEFASAVKSTH ASVSVSASES TSASTSTSEA VSTEASEFVS AVDSLSQVTSNGSTTKEDAS TFVSTVDSLK DKASNNGTPS EFESVVKSVH GSMSASASASTSASTSASTS TSEAASAEAS ELESVRKSLS NGASNGSTAR EGASTFVSTVDSLKDKASNN GTASEFESVV KSVHGSTSAS ASASTSASTS ASESASTEASEFVSAVASLS SSAWNGSTTG EGASTFVSTV DSSKDSASDK ASPSESESVVKSVHGSTSTS ASVSASASTS ASTSTSEAVS TEASEFVSAV NSLSSEASNGSTTREGASTF VSTVDSLKDK ASNNGTASEF ESVVKSVHGS MSTSASVSASESTSASTSTS EAVSTEASES ASISVSMSVS ASTSASMSVS VSNSVSVSDSISVSASTSEP NSVSTSMSSS LSTSASTPSE ITSSSSSSDS ATVQKVVSKDEQHATNKVEK LPDTGQSTTQ TGLLGGVGAL LTGLGLLKKS RKQKDEETSS HE SEQ ID NO: 13atgaaaaagtctagaaaaaagcgtatcgattttttacctaaccgtcaaaatcgatatgcgatacgtcgtttttcagtaggcactgcgtcaattctcgttggagcaacattaatttttggaattcattcaaatgatgcatcggcagcagtagaagacgcaacatctcaagaagcaggaacaactaacgaaaattcaaatagtacagaagaagcaacaacaaacgaaagtacaactgttgaagcaccaacaagtgaagaagcaacaacggaagagcaatcagtagaggcgccaacaagtgaagaagtaacaacggaagagcaatcagtagaggcaccaacaagtgaagaagtaacaacggaagagcaatcagtagaagcgccaacaagtgaagaagtaacaacggaagagcaatcagtagaagcgccaacaagtgaagaagtaacaacggaagagcaatcagtagaggcaccaacaagtgaagaagtaacaacggaagagcaatcagtagaggcaccaactagtgaagaagtaactacggaagagcaatcagtagaagcaccaacaagtgaagaagcaacaacggaagagcaatcagtagaagcaccaacaagtgaagaagcaactacaaaaactcctgtaaaagaagaaacatcctcaacacaagaaaattcacccacgactacactagaagaacaattttcaaatgaattcaatcagttaacatctacagaagataaaacaaactacacacgtgaatatttaactcaaaacacaaatctttcggcagaacaagtggaagcaacagttgaacgcttgaatttaagtcaagaaaatgtaacagcccaagatatctatttcgcattacttaaagatttagctgatcaacaagatgccttattaccacgtgtaacacttttggccgctagagattctgagctcacaaacgaagcgtctatcgctttaactgaaaatagtccaatgttccgcgcagcattagcgaatagtccttctggcaatgatgtggtgtcagaagaagataatattattgtggctgatgcactcgcaaatggatacatcaattcacaaacagatgcaacaaatgcggcaaatacattgtctggtcgtgcatgggttgtggatacagggacaccagcgacaatgtcaaacggcttaacagctgttccagaaggcacaaaagtctacatgcaatggattgatacagatggcgcggtttcaccagtgtatcaagcaagcacaacaaataaattgagttcaagtggtggtagccaagtaggtccaggtgcatatgcatttgatttacgtgaagcatggatagactcaaatggcaaagcgcacagatatgaagcgtcaagtggccaatattatcgtttatggattgatgactacaaaacagtagatgggaatacggcaaccatgttacgccaagcaggtggtttcttccctggttcatatgttaattcggtgacaggtaacaatattggtcaattcccacttatcggaacgaacatgcaacgtacaggtatctttatgggtgtgataccaacgaacgattacatgactacagatacaagcaattggattcaagataatgaaggacctatttcaaacccagcagtaacgagcacaagtgaatttgtcagtggtaaagtatggtctgagacaggttcaggtgactatgcgaactctgcgacaggtccaaactttaactcaggtgatattgcacgtgaaggttatcaagttgtcatgtcttcattaacaagtgctggtgcccaagcgtataaagcacaagtcgaatcgttgccaacagaccaacaagcggcagcagcacaccaattattcaaagaccacccagaatttatttctgcgacagtgacgggtaaaactgatgcaaacggtgcgtatacattacgtttcccttcaggctcattgagtaaagattatctttatggttatgtgatggataataagggcaacttggttaagggctattcatcattcacgtcacctttattccgttcgcctaacagtaacttatctttcgcgccacaaacagcgccatatcatagaccagccaaaaatgcttgggtgaatgtgaactttgcgcttgtagaaacaattgaaacaagtatagacatcacgaactttgatgtgacagccaacccagcgcaacgtggtgatacggctatcattgatgtgacttctacagcattgtcaccattacctacgcatgttgagtggagagattcaaaagggaatgtcgttcaaaaaagtggagatgtcactacggtagaagaagctgaaacggcaggcacatttactattcctgatgatgcgaaaacaggtgaaatctatacagtttatattgtttcaggaggcaatgaagttgcagcagactcactgattgtccaagtgcaagaaaatgcggcaacctatgaacctgtatatccaacaacaacagttgaacaagaccaaactgtaacaattcctacacctacaaatgaagatggtttagcattaccagacggaacaaagttcgaaggtggcaacaatgtacctgaatgggcaactgtgaatgaagatggttctatttcaatttcaccaaatcaagatgtggaaaaaggtaactataatgtgcctgttgtcgtcacatatccagatggttcaaaagaaacagtatttgcaccagttttagttcaagaagctgttccaactgcagaacaatacgatccaacaattgaaacaattaataaggaatatggtactactgcaacagaagatgaaattaaaggcgcaatcacaattccggattacccaacagatggagatcaaccaacaatcacgattgacgacccaactcaaattccaaatggaacagaagaaggcacagtgaatgtaggtgtcactgtcacttatccagatggttcaacagacaaattaacagtaccagtcgttacaggtaagcaagcggataacgataagtacacaccagaaacaacaccaattacgaaagacttcggtacaggtgtaacagaagacgaagtgaaaggtgcagtcactgttccggattacccaacagatggagaccaaccaacaattacgattgacgacccaagtcagttgcctgatggttcaaaagaaggaacaacggatgtcgacgtaacagtggaatatccagacggcacaacagatcacatcacagttccagtgactgttggaaagcaagcggataatgataagtacacaccagaaacaacaccaattacgaaagacttcggtacaggtgtaacagaagacgaagtgaaaggtgcagtcactgttccggattacccaacagacggtgaccaaccaacaattacaattgatgatccaaatcaattaccggacggttcacaagaaggtacgactgatgtaaatgtaacagtggaatatccagatggcacaacagatcacatcacagttccagtgactgttggaaagcaagcggataatgataagtacacaccagaaacaacaccaattacgaaagacttcggtacaggtgtaacagaagacgaagtgaaaggtgcagtcactgttccggattacccaacagatggagatcaaccaacggttacaattgatgatccaaatcaattaccggacggttcacaagaaggtacgactgatgtaaatgtaacagtggaatatccagacggcacaacagatcacatcacagttccagtgactgttggaaagcaagcggataatgataagtacacaccagaaacaacaccaattacgaaagacttcggtacaggtgtaacagaagacgaagtgaaaggtgcagtcactgttccggattacccaacagacggtgaccaaccaacggttacaattgatgatccaaatcaattaccggacggttcacaagaaggtacgactgatgtaaatgtaacagtggaatatccagatggcacaacagatcacatcacagttccagtgactgttggaaagcaagcggataacgataagtacacaccagaaacaacaccaattacgaaagacttcggtacaggtgtaacagaagacgaagtgaaaggtgcagtcactgttccggattacccaacagatggagatcaaccaacggttacaattgacgatccgagtcagttaccagatggctcacaagaaggcacaacagatgtgaatgtaacagtggaatatccagatggcacaacagaccacatcacagttccagtgactgttggtaagcaagcagataacgataagtacacgccagaaacaacaccaattacgaaagacttcggtacaggtgtaacagaagacgaagtgaaaggtgcagtcactgttccggattacccaacagatggagaccaaccaacaattacaattgacgatccgagtcagttaccagacggttcacaagaaggtacgactgatgtaaatgtaacagtggaatatccagatggcacaacagatcacatcacagttccagtgactgttggtaagcaagcagataacgataagtacacaccagaaacaacaccaattacgaaagacttcggtacaggtgtaacagaagacgaagtgaaaggtgcagtcactgttccggattacccaacagatggagaccaaccaacaattacaattgacgatccgagtcagttaccagacggttcacaagaaggtacgactgatgtaaatgtaacagtggaatatccagatggcacaacagatcacatcacagttccagtgactgttggaaagcaagcagataacgataagtacacaccagaaacaacaccaattacgaaagacttcggtacaggtgtaacagaaggcgaagtgaaagattcaatcacaattcccggttacccaacagatggagaccaaccaacaattacaattgacgacccaagtcagttaccagatggttcacaagaaggtacgactgatgtcgatgtaacagtggaatatccagacggcacaacagatcacattacagttccagtgactgttggaaagcaagcagataacgataagtacacaccagaaacagaaggtgtcaacaaagatcatggtacgtcagtaacagaagatgaagtgaaaggtgcagtcactgttccgggatacccaacagatggagatcaaccaacggttacaattgatgatccaagtcaattgccggacggttcacaagaaggtacgactgatgtaaatgtaacagtggaatatccagacggcacaacagaccacattacagtcccagtaactgttggtaaacaacctactaaagataacggggctacagataatgatggcgacatgaatcaaggcacagatgaaggaaatagtgctactgatcatggcgacaatgtaaaacaagattcaaacggaaactatacgccggttgaacaacgtgacaatcatgcgacttcacctgcaacagatatggatccaatgccaagcaatagccaaacaacttttgatggcataaatgcaaaaggttcaacttcagagaaagcaaaccataaacaacagtctgagcaattaccagacacaggtgaaagcaatacacaaaatggtgcacttttaggcggattatttgcagcacttggaggcttattcttaatcggcagacgtcgtaaagaaaaagaaggcaaataaThe protein sequence translated from SEQ ID NO 13 is designated SEQ IDNO: 14 and is shown below:

SEQ ID NO: 14 MKKSRKKRID FLPNRQNRYA IRRFSVGTAS ILVGATLIFG IHSNDASAAVEDATSQEAGT TNENSNSTEE ATTNESTTVE APTSEEATTE EQSVEAPTSEEVTTEEQSVE APTSEEVTTE EQSVEAPTSE EVTTEEQSVE APTSEEVTTEEQSVEAPTSE EVTTEEQSVE APTSEEVTTE EQSVEAPTSE EATTEEQSVEAPTSEEATTK TPVKEETSST QENSPTTTLE EQFSNEFNQL TSTEDKTNYTREYLTQNTNL SAEQVEATVE RLNLSQENVT AQDIYFALLK DLADQQDALLPRVTLLAARD SELTNEASIA LTENSPMFRA ALANSPSGND VVSEEDNIIVADALANGYIN SQTDATNAAN TLSGRAWVVD TGTPATMSNG LTAVPEGTKVYMQWIDTDGA VSPVYQASTT NKLSSSGGSQ VGPGAYAFDL REAWIDSNGKAHRYEASSGQ YYRLWIDDYK TVDGNTATML RQAGGFFPGS YVNSVTGNNIGQFPLIGTNM QRTGIFMGVI PTNDYMTTDT SNWIQDNEGP ISNPAVTSTSEFVSGKVWSE TGSGDYANSA TGPNFNSGDI AREGYQVVMS SLTSAGAQAYKAQVESLPTD QQAAAAHQLF KDHPEFISAT VTGKTDANGA YTLRFPSGSLSKDYLYGYVM DNKGNLVKGY SSFTSPLFRS PNSNLSFAPQ TAPYHRPAKNAWVNVNFALV ETIETSIDIT NFDVTANPAQ RGDTAIIDVT STALSPLPTHVEWRDSKGNV VQKSGDVTTV EEAETAGTFT IPDDAKTGEI YTVYIVSGGNEVAADSLIVQ VQENAATYEP VYPTTTVEQD QTVTIPTPTN EDGLALPDGTKFEGGNNVPE WATVNEDGSI SISPNQDVEK GNYNVPVVVT YPDGSKETVFAPVLVQEAVP TAEQYDPTIE TINKEYGTTA TEDEIKGAIT IPDYPTDGDQPTITIDDPTQ IPNGTEEGTV NVGVTVTYPD GSTDKLTVPV VTGKQADNDKYTPETTPITK DFGTGVTEDE VKGAVTVPDY PTDGDQPTIT IDDPSQLPDGSKEGTTDVDV TVEYPDGTTD HITVPVTVGK QADNDKYTPE TTPITKDFGTGVTEDEVKGA VTVPDYPTDG DQPTITIDDP NQLPDGSQEG TTDVNVTVEYPDGTTDHITV PVTVGKQADN DKYTPETTPI TKDFGTGVTE DEVKGAVTVPDYPTDGDQPT VTIDDPNQLP DGSQEGTTDV NVTVEYPDGT TDHITVPVTVGKQADNDKYT PETTPITKDF GTGVTEDEVK GAVTVPDYPT DGDQPTVTIDDPNQLPDGSQ EGTTDVNVTV EYPDGTTDHI TVPVTVGKQA DNDKYTPETTPITKDFGTGV TEDEVKGAVT VPDYPTDGDQ PTVTIDDPSQ LPDGSQEGTTDVNVTVEYPD GTTDHITVPV TVGKQADNDK YTPETTPITK DFGTGVTEDEVKGAVTVPDY PTDGDQPTIT IDDPSQLPDG SQEGTTDVNV TVEYPDGTTDHITVPVTVGK QADNDKYTPE TTPITKDFGT GVTEDEVKGA VTVPDYPTDGDQPTITIDDP SQLPDGSQEG TTDVNVTVEY PDGTTDHITV PVTVGKQADNDKYTPETTPI TKDFGTGVTE GEVKDSITIP GYPTDGDQPT ITIDDPSQLPDGSQEGTTDV DVTVEYPDGT TDHITVPVTV GKQADNDKYT PETEGVNKDHGTSVTEDEVK GAVTVPGYPT DGDQPTVTID DPSQLPDGSQ EGTTDVNVTVEYPDGTTDHI TVPVTVGKQP TKDNGATDND GDMNQGTDEG NSATDHGDNVKQDSNGNYTP VEQRDNHATS PATDMDPMPS NSQTTFDGIN AKGSTSEKANHKQQSEQLPD TGESNTQNGA LLGGLFAALG GLFLIGRRRK EKEGK SEQ ID NO: 15atgacagaacgaaaatccccttcatctcaaaacatgcgtcatcgtttagtcaaagctggtactgtccttttattggttggtagtggactgcaaatgccttcaacattgtcacacgaaatgacagcgatagctcagacagatgcgactgatgatttgaaaacattacgtgaaaatgcagataaaaaagtgaaagcgttacaatatttaaatacggattataaaaatgaatttcttgcgttaattcgtgaatatgatacgtcgtcaaaaaatattgaagtggttgttgacgaagcagaagcagccaatcgtctagctcatgacgctcaatcggacgatgaaatacaacctgaattagatgccattgatgaaaaaattagcgcgttaaaggcaaaggttgatgaaggtcaacgagaatcaactgaagcgcgtcaagatgtaacgtcaacagagacaaagagtgctgaatcagaaggaagagagccatccactgaaggcgagagcaaagtaaaggagtcatcttcagcacaaacgattgtagcacctcatcatggtcaacaagatgtgagcgcactgaaagaccatattaagaacgatgtcgatacacttaaacaagactatgcaacgcaagacaagcaagtgacaccactccagggcattgacagtgcaatcacacgcattgaccatttcgtttcagaaagcgtggatcacaagtctgacaattattttgaagaaaaacgtcaacatttacaaaactttgaacaagacattaaaaaacgtacggacatttctgggactgagaaggcgactttgcttgatgatgcgaaaacggtagccaaccaactgaacgcgcaaaatgatacgattttaactgaacttcaacagcatgacgataaacgtgcagcagttgaatcgatattaggtgagatttttaatgcacaagaagcggctgaacgtgcgaaacagatagatgttaaaggtaaaacagatcaacaattggcaaacgaaattcatcaacaagcggacggacttatcaaaacgtcgagtgatgatttattgttaggaatgttggaaaataattcaaatacacaaggtctagtggaaagcattttacgaacacgctttgacaaacaagaagcgcacaaaattgccggcgaaatcatgcaaggcaagccttcaaatacagcgatactcgaccgcttgaaagaccattttaaagcgaatggtaaggcgagtggagatgatattttaaatgcgttaattaataatacggatgcagatgctgaagtgattgaatcaattctagggggccgtcttaatgcagaaaatgcaaaattgattgccgatcgtgtacagcaagataaaaagaagacacatcaaaacttaaaggcgattgaagacgaacttagtgcgcaagcgaatcgattgttaacgttacggaagcaattgcaacaaatccgtcataatacgcaaacagatatgaatgacttgtttgcaccactgcgtcgtattgcaaatattctcggtggtggtttaaatcgtgacgacattcactcttcaggtcgtacgaatgacaaattgcagcaactgttaaatcgtgatcattcgttgttaggtcgtggtggtgatttattcaaacatgattttgcgccaaagccgaatatcgatccatatcaagcgattaatagtcaaacggcatcagaaggttttttagatggtttatttgatcaaaatggcgatttcaatttaccgaatacaggtgaaatagtgaagcggacttggctaccgttgggtattttagtcgttgcaatcggtgtactgatcttaacggtgagatttcataaaaaaacacgcaaacaataaThe protein sequence translated from SEQ ID NO 15 is designated SEQ IDNO: 16 and is shown below:

SEQ ID NO: 16 MTERKSPSSQ NMRHRLVKAG TVLLLVGSGL QMPSTLSHEM TAIAQTDATDDLKTLRENAD KKVKALQYLN TDYKNEFLAL IREYDTSSKN IEVVVDEAEAANRLAHDAQS DDEIQPELDA IDEKISALKA KVDEGQREST EARQDVTSTETKSAESEGRE PSTEGESKVK ESSSAQTIVA PHHGQQDVSA LKDHIKNDVDTLKQDYATQD KQVTPLQGID SAITRIDHFV SESVDHKSDN YFEEKRQHLQNFEQDIKKRT DISGTEKATL LDDAKTVANQ LNAQNDTILT ELQQHDDKRAAVESILGEIF NAQEAAERAK QIDVKGKTDQ QLANEIHQQA DGLIKTSSDDLLLGMLENNS NTQGLVESIL RTRFDKQEAH KIAGEIMQGK PSNTAILDRLKDHFKANGKA SGDDILNALI NNTDADAEVI ESILGGRLNA ENAKLIADRVQQDKKKTHQN LKAIEDELSA QANRLLTLRK QLQQIRHNTQ TDMNDLFAPLRRIANILGGG LNRDDIHSSG RTNDKLQQLL NRDHSLLGRG GDLFKHDFAPKPNIDPYQAI NSQTASEGFL DGLFDQNGDF NLPNTGEIVK RTWLPLGILVVAIGVLILTV RFHKKTRKQ SEQ ID NO: 17atgttaaaaaaattaattgttacaggtttgattgctacagcggcgacacaagtttatgcgcatgacacgcaagcggcggaaaagggtgctacagatgctccgaatgtgatggttaaggatgaggcgaaaaaagaagtgacaccgataatccataaaccgacttgcatttacccgcatctagaaggcgaagatgatgctgcgtatttaaaacgtatggcaacgaatccaccagaaggcgcagtgccgtacggtgtattgaataaagatggatcgattacagaaccgaatacaaatccacattttgatgttttaaaaattgaagatccaaatgcgatgaaagatttggttgatacaccggcagatgatcaagatacggtaccgagtgatttacaaattgaaccaccagcattaataggaccagctactaaacatacggatggtacgggagacgcaaaatctaatgatgaccacaaagtaacaaaatcttcgggagcgtcagcccaagatatgaagaaaaaagacgtgacaacacaaactgcacaaccaaaagcagataaaaagatggcgactgcaaaagtagcaccagcgaaacaacaagataaagcagccaaaatgttaccagcagcaggggaaccacaagtgaatgcaatcagtcaaacagcacttgcactttcaatgatcgcattaggtgtcatcgcgttctttacacgacgacgcaaa acaaattaaThe protein sequence translated from SEQ ID NO 17 is designated SEQ IDNO: 18 and is shown below:

SEQ ID NO: 18 MLKKLIVTGL IATAATQVYA HDTQAAEKGA TDAPNVMVKD EAKKEVTPIIHKPTCIYPHL EGEDDAAYLK RMATNPPEGA VPYGVLNKDG SITEPNTNPH FDVLKIEDPNAMKDLVDTPA DDQDTVPSDL QIEPPALIGP ATKHTDGTGD AKSNDDHKVT KSSGASAQDMKKKDVTTQTA QPKADKKMAT AKVAPAKQQD KAAKMLPAAG EPQVNAISQT ALALSMIALGVIAFFTRRRK TN SEQ ID NO: 19atggtagaatataaaaaagaacatagcgtaaagcgactattaaaattaggaatcggttcaacgagtattttatgtgttgtatcacctcttttattaacacatgacgttgttcaagcagcagatatcaataacaggatgccagctttgaatacattgaagaccacttcttcatatgatcaaagggcacacatggatgaattacgaaacgccattacttcagatagtgacactactcaaacaccatcattcaatgagataactgtgtcttcaactaatgaaacggatgcagcgtcaacggaaaatgtgaacccgagtgatgaggtcccggcaaaggatgaaagtgaatcaacgacaccgagtacagaacaagacacatctatagaagaaacgggtactgaagaagtgccatctcatgaagacaatcatcacaacaccccaagtcaagaagagcaaccgtctccgcctgatcaaccaggaacaaacaaagatgaagagagtggagaaaaaccgaataaagaaaatcatcggaagccgaatcaaccgaacaaagaccaaccttcaaaagatgagaataaaaaacctgacaaaggaaacaaaccagcaccaccgtctaaaatgccaaatcgcccggatcaaaaggaagatggttcaaacaacaccccaccacctgccactgataacggtggaaacagtaatgacggtacaacaacgggtcccaatggtggaggtggcagtgaagcaagtccaccaccgaatgagcaaccgtcaaatggcaatgcaagcgatacccatcaaaacggttcagtttcaagcaccaatcattcgaatcagtatggtacatcggcttatgatgaatacgcaggtttattgaataataattataaatataatccattgtttaaagaagaggttgcgcgtttaagtcaatttggaagtcaagatcaacatgatattgcaagtttgagtcgtaaagaacaattttctcaaaatgcatttttagatgacttgcaacaaagtacagattattttagatatcaatattttaacccgctttccacagagcaatactatcatcgtttagataaacaagtattagcactcgttacgggggaatttggttcgatgccagatttcaagaaaagtggtgataagtcattggttaataagcatcagcaagataaagtgaagaaaattgaacagcaaggagaaaatattaatacgcatcatatgaaaaatacgaaagaagatacaggaaaatcattaagttacaagccgatgatatatattggcattgtcatggtcggttttgtcggcctgatcagtatgattttatggaaacgactgcatcatttttggaaataaThe protein sequence translated from SEQ ID NO 19 is designated SEQ IDNO: 20 and is shown below:

SEQ ID NO: 20 MVEYKKEHSV KRLLKLGIGS TSILCVVSPL LLTHDVVQAA DINNRMPALNTLKTTSSYDQ RAHMDELRNA ITSDSDTTQT PSFNEITVSS TNETDAASTE NVNPSDEVPAKDESESTTPS TEQDTSIEET GTEEVPSHED NHHNTPSQEE QPSPPDQPGT NKDEESGEKPNKENHRKPNQ PNKDQPSKDE NKKPDKGNKP APPSKMPNRP DQKEDGSNNT PPPATDNGGNSNDGTTTGPN GGGGSEASPP PNEQPSNGNA SDTHQNGSVS STNHSNQYGT SAYDEYAGLLNNNYKYNPLF KEEVARLSQF GSQDQHDIAS LSRKEQFSQN AFLDDLQQST DYFRYQYFNPLSTEQYYHRL DKQVLALVTG EFGSMPDFKK SGDKSLVNKH QQDKVKKIEQ QGENINTHHMKNTKEDTGKS LSYKPMIYIG IVMVGFVGLI SMILWKRLHH FWK SEQ ID NO: 21gtgattacaaataaaaatatatatagtattcgaaagcataaacttggcgtggcatcattcttattggggacattatttgttgtagggcatgcaaataatgctgaagcttcagaagtgagcgcaacaacacaagaacataatgtcgagactgagcaaacaaaaactgagggcgaactaacaactgaggtagcacaacaagcagtcagcgaatcagcacctatagctgaaaacatgcagaaaacaacatcagtggcaagtgaaaatgcgaaagaggttacagcttctgatagcacacaagaagtcacaaaaactgaagcaaaagatacagcaacaatgaaagattcagaaattgcacaacctgtatcagaagtgaataaacctgttactcaaacagctgcacccgtagcagaaccatcaacagcaaacaaacaaacttcaccacgacaagtacaagaacttactgcaccaatggacacaaaagtaattaatgtagaaaacggaacagatgtgacaagtaaagtgaaagttgaaaaatcgtcaattacagggcatcagaataaagataaaacatatcatcaatcgaacactgtaaatccacataaagctgaacgtgtgacattaaattatgattggtcatttgaaaatggaattaaagctggtgattattttgacttccaattaagcgataatgtcgatacaaatggaatatcaacaataaaaaaagtcccacacattatggatagtcaaaatagcgaacaaattattgcttacggggaaattaatgaaaacaaccgtgtccgttaccgatttatggactatgtaaatcaaaaagaaaatttaaaaggtaaattgtcattaaacttatttattaaaccagataaagttcaagatgaaggaaaaatcactgtcacttcacaattgggcaaggaaatgacaagtcaggaatttgacattaaatatattgatggtgtaaaaagcccttcaggtatcacattaaacggtcgtcttgatgaattatcaaaagcagatcaatcatttacgcattattctatatttaaacctaagcataataacttaactaatgtaactttaagaggcacagtttcaaataacgcacagcaaaatgaaaaaaatggtcaagttaatgtttacgaatatattggtcaaggagaattgccacaaagtgcttatgccaatgtaaatgatacgaagcagttcaatgacattactaagagtatgaaatcaatcaaaaataacagtaatggctatgaaattacttttgacatgaacaaagacaatcatccttatatcatagtatatcaaggtcactttaacaataatgcaaaagactttgatttctcaacaaatgcgacaggttatcaaaatttaaatcaatcggaatatagttattattggccttacaattattcattcaatttaacatgggataatggtgttgctttctactctaataatgcaagtggggaagggaacgacaaacctgtaccgccgacttatggatatagtccgacagtaaatacaattcaagatactcatgcggattatcctgtaatgactttccaacaacctggaactctagaggagacagaagacagtatgccaatcactacacttaccgaatctggtgaggatcgtggtgaaaatacttctccaattatcgagacaacagaagattcacagcctgttgagtttgaagaagagacaaatcatggcattcaagacgtgacacttcatgcagatgctgttgattttgaggaagaaacaaaccatggtgaacaagacacggtacaccactctgatgtcgttgaatacgacgaagatacgacaactggcatgttaacaggtgccatttctgaccatacaacagaagaaggcacgatggagtacacaactgatggcttattgattgagtttgatgatgaaatgaatcctaatgtgagcggtcagtacgatgacatcacaacggatacgatagaggaatcatctcatattgacacattcactgaacttgaatctgaatttggtcaacatgacggtatagtgacatttgaagaagatactatcgttgagaagccgaaaacagaaaagggtaaccgagtaccacttgtaattgatttatcaacaccaaaacataaccatcagttcaatattcaacctaccgatccaaatattgatacctctgctacgtatcgaattggcaattttgtatggcgcgatgaagatcacaatggcgtacaaaatgatggtgaacatggtcttgaaggtgttcttgtcacacttaaaacagctgatggtgtcgttttaaatacaacgacaagtgatgccaatggacactaccagttcactaatgttcaaaaaggaaaatatattgttgaattcactacacctgaaggttatgaagcaacaagcaaacatactacagcgaatactgaaaaagactctgatgggttaatcgcaaatatcgatgttactcaagatgatatgtcaatcgatgctggtttcttcccgttagaaaactggaatcctcagccagagccgaaaaaccctgatgatagagagaaaccggcacctgagcaacctgatgtacctcagccagaaccgaaaaaccctgatgatagagagaaaccggcacctgagcaacctgatgtacctcagccagaaccgaaaaatcctgatgatagagagaaaccggcacctgagcaacctgatgtacctcaaccagagccgaaaaatcctgatgataaagagaaaccggcacctgagcaacctgatgtacctcaaccagagccgaaaaatcctgatgataaagagaaaccggcacctgagcaacctgatgcacctcaaccaaagccgatgctcccaggtgaaaaggtgaaacccaaaccaactcatcccggtgaagctatgcaaacaacacctcaggacaaatcaacatctcaaacagatgaagcacttcctaaaacaggtgaatcatcatcacaatcatctgctttaatcttcggtggtttactcagtctattaggacttggtttattacgtcgatcatctaaacaaaaccgttcttcaatgaaataaThe protein sequence translated from SEQ ID NO 21 is designated SEQ IDNO: 22 and is shown below:

SEQ ID NO: 22 VITNKNIYSI RKHKLGVASF LLGTLFVVGH ANNAEASEVS ATTQEHNVETEQTKTEGELT TEVAQQAVSE SAPIAENMQK TTSVASENAK EVTASDSTQE VTKTEAKDTATMKDSEIAQP VSEVNKPVTQ TAAPVAEPST ANKQTSPRQV QELTAPMDTK VINVENGTDVTSKVKVEKSS ITGHQNKDKT YHQSNTVNPH KAERVTLNYD WSFENGIKAG DYFDFQLSDNVDTNGISTIK KVPHIMDSQN SEQIIAYGEI NENNRVRYRF MDYVNQKENL KGKLSLNLFIKPDKVQDEGK ITVTSQLGKE MTSQEFDIKY IDGVKSPSGI TLNGRLDELS KADQSFTHYSIFKPKHNNLT NVTLRGTVSN NAQQNEKNGQ VNVYEYIGQG ELPQSAYANV NDTKQFNDITKSMKSIKNNS NGYEITFDMN KDNHPYIIVY QGHFNNNAKD FDFSTNATGY QNLNQSEYSYYWPYNYSFNL TWDNGVAFYS NNASGEGNDK PVPPTYGYSP TVNTIQDTHA DYPVMTFQQPGTLEETEDSM PITTLTESGE DRGENTSPII ETTEDSQPVE FEEETNHGIQ DVTLHADAVDFEEETNHGEQ DTVHHSDVVE YDEDTTTGML TGAISDHTTE EGTMEYTTDG LLIEFDDEMNPNVSGQYDDI TTDTIEESSH IDTFTELESE FGQHDGIVTF EEDTIVEKPK TEKGNRVPLVIDLSTPKHNH QFNIQPTDPN IDTSATYRIG NFVWRDEDHN GVQNDGEHGL EGVLVTLKTADGVVLNTTTS DANGHYQFTN VQKGKYIVEF TTPEGYEATS KHTTANTEKD SDGLIANIDVTQDDMSIDAG FFPLENWNPQ PEPKNPDDRE KPAPEQPDVP QPEPKNPDDR EKPAPEQPDVPQPEPKNPDD REKPAPEQPD VPQPEPKNPD DKEKPAPEQP DVPQPEPKNP DDKEKPAPEQPDAPQPKPML PGEKVKPKPT HPGEAMQTTP QDKSTSQTDE ALPKTGESSS QSSALIFGGLLSLLGLGLLR RSSKQNRSSM K SEQ ID NO: 23atggcatttgatggtatgtttacaagaaaaatggtagaagatttacaatttctcgtttctgggcgtattcataaaatcaatcaaccggaaaacgatacaatcatcatggttataagacagcaacgccaaaatcatcaattgttgttgtcgattcacccgaattttgcacggattcacctcactacaaaaaaatatgataatccatttgaaccgccgatgtttgcgcgcgtctttcgtaaacatttagaaggtggacgtatccttgccattcgccaaatcggaaatgaccgtcgcatcgaaatggacgtggaaagtaaagatgaaattggtgacacgattcatcgtacagtgattttagaaattatgggcaaacatagtaatctcattctcgttaatgaagaacgtaaaattttagaaggttttaaacaccttacaccaaatacgaatcaatttagaaccgtgatgccaggttttcaatatgaagtgccgccaacacaacataaacagaacccttatgcatatactggtgcgcaagtgctccaacatattgatttcaatgcgggcaaaattgatcgccaactgcttcaaacgtttgaaggtttttcaccgttaatcacaaaagaaatcacatcaagacgccattttatgaccacacaaactttacctgaagcttttgacgaagtgatggccgaaacgaaagcgacaccccaaccggtatttcataaaaataacgaaacaggtaaagaagacttttattttatgaagttacatcagttttacgatgattgcgtcacatatgattcactccatgaactgctcgaccgtttttatgatgcacgcggtgaacgtgaacgcgtcaaacaacgtgcaaacgatttagtcaaactcgtccaacaattacttcaaaaatatcaaaataaattaagtaagctcgtcgatgaacaagcggggactgaagaaaaagaaaatcaacaattgtacggcgagttaatcacagcgaatatttatcaactcaaacctggagatcgccagttagaaacagtaaattattatacaggagaaaacgtgactattccgttaaatccacaaaagtcacctgctgaaaatgcgcaatactattacaagcaatacaaccgaatgaaaacacgtgagcgcgaattgacccatcaaattactttaacggaagaaaatatcgcttattttgaaaatatcgagcaacagttgtcacacattcaagttcatgaaattgacgatattcgtgaagaactagcagaacaaggctttatcaaacaaaagaaacagcagaaaaagaaaaagcaacaaaaaatccagttacaatcctacgtttcgactgatggcgatacgattttagtcggtaaaaataataagcaaaatgattatttaacgaataaacgtgcgcaaaaatcgcatttatggttccatacaaaagatatcccaggaagccatgtcgtgattttaaatgatgcgccaagtgacaaaacgattgaagaagcggcgatgattgcagcgtacttttcaaaggcggggcaatcgggacaaattccagtggattatacaacaattcgcaatgtgcataagccgagtggcagtaaacctggatttgtaacgtacgataaccagaagacgctttacgcaacgccggattatgacatgattcgtcgattgaaagctgaagaagcgtaaThe protein sequence translated from SEQ ID NO 23 is designated SEQ IDNO: 24 and is shown below:

SEQ ID NO: 24 MAFDGMFTRK MVEDLQFLVS GRIHKINQPE NDTIIMVIRQ QRQNHQLLLSIHPNFARIHL TTKKYDNPFE PPMFARVFRK HLEGGRILAI RQIGNDRRIE MDVESKDEIGDTIHRTVILE IMGKHSNLIL VNEERKILEG FKHLTPNTNQ FRTVMPGFQY EVPPTQHKQNPYAYTGAQVL QHIDFNAGKI DRQLLQTFEG FSPLITKEIT SRRHFMTTQT LPEAFDEVMAETKATPQPVF HKNNETGKED FYFMKLHQFY DDCVTYDSLH ELLDRFYDAR GERERVKQRANDLVKLVQQL LQKYQNKLSK LVDEQAGTEE KENQQLYGEL ITANIYQLKP GDRQLETVNYYTGENVTIPL NPQKSPAENA QYYYKQYNRM KTRERELTHQ ITLTEENIAY FENIEQQLSHIQVHEIDDIR EELAEQGFIK QKKQQKKKKQ QKIQLQSYVS TDGDTILVGK NNKQNDYLTNKRAQKSHLWF HTKDIPGSHV VILNDAPSDK TIEEAAMIAA YFSKAGQSGQ IPVDYTTIRNVHKPSGSKPG FVTYDNQKTL YATPDYDMIR RLKAEEA SEQ ID NO: 25atggtcaaaaaatttggttataaaacacctacaatcgttgcacttactttggctggaactgcattttctgcacaccaagccaatgccgctgaacaagttgcacctgaaaaaacacctacgaatgtacttgatgatcaatacgcattaaaacaagctgatgatgcgaaacaaacgacacaaggaacaacacttgcaggttcaaaagaatacaaggatccttcacaaattgatacgactcaagtcgatacagcagcacaaactgaaacgcccgtagaaggagggcaacaagacgcacaacaacctactacaactgatgaagcgacatcaacagatcatactgtatcaaaaggtacaaacgaaagtgcatcacctgcaacagcttctatagatgaaggaacattaaacgcacaagtcaattcagatgaaacggctactaaccgtacacaagacgtcactgaaaatgtgacaaaatatccttatcattcaagtgaaatcgatacacatgaagacgcaactgtgtcaccagatacatatcatgcactggacacgcatgcgcaacaaccttcagcaatggatgtaagcgattcaacatcagcacaaactgaagcgacgcaagtaaatacgtcaacaaatgtaaatgacaaagaggccgtttcgacaacagaagatgcacctactacacaacttcaagcagctgtacaatctgaagccaacaaagaagcgaaggcaactactgaaacagctcaaaataaaacacctcaagttgaaaagaaagcaacagcaactcaaaatacagcacagttagcaacggggcatcaggatattactgacaaagtctcaaaacgcgtagcagtgacaaatgaaacgaaagcggatgccacaacagcgaaaacacaagcacctacttcagtgacacatcaagctgatacacaagcaaaaacgataacagacaagaaggcaacaacttacagtgcacaaaccgcaactgaccaagacataaatgcgaatccggacggtccaacacctccacgcgttggcggtaaagggggtccccctgcttcactttcactccaatcgactggtcaaacagcattccgttcagctgtcgctagtaaaccgagtgcatatcaacctaaagtgaaatcgtctattaatgactatattcgtaagcaaaactacaaagtgcctgtatatgaagaagattattcaagttacttccctaaatacggttatcgtaatggtgtcggtaaacctgagggcatcatcgtgcatgatacagcaaatgacaactctacaattgatggcgaaatcagttacatgaaaagaaattatcaaaatgctttcgtacatggctttattaatggtcaacgtattgttgaaacgcaacctacagattatttagcatggggtgcaggtgcgattgcgaatgaacgctttattcatatcgaactcgttcatgttcacagtaaagaagatttcgcacgtcaaatgaacaatatggcagattatgcggcgacgaacttacaatattatggcctttctccagatagtgcggaatatgatggtcgtgggacagtttggacacatgatgctgtttctagatttttaggtggtacagaccataccgatccgcacggctatttaaaacaacatggttattcctttgatgcgttgtatgatttaatcaatgaaaaatatcaagtgaaaatgggttatgcctcacctgctaactcgtcttcaaaaccatcaacaaatactggcttaacagttaaaaacacaacaggtttcggccgtattaacacaacaaatagcggtttatatacgaccgtttatgatcaaaaaggtaaagcgacgaatcaaacgaatcaaacgttaaaagttacaaaagaagcgacgttaaatggcaacaaattctatttaatgagtgatgcaaaatctaatcaaacactcggttgggtcaaatcaaacgacgcaacatatcaagctgcccaagctgagaaaaaagtaacgaaaacgtatactgtcaaaccaggaacaacagtatatcaagtgccttggggtgcctcatctcaaacagtaggcaaagctccaggtacgtcaaaccaatcattcaaatcaacgaaagaacaaactgttgcgaaaacgaaatggctttatgggacagttggcaaagtgacaggctggattaatgcaagtagtgttgtagcaaatgatcaaaaaccatcgacgaataccgcactaaaagtaacaactgacactggtctcggtcgcattaaagacaaaaatagtggtttatacgcaacggtatatgataaaactggtaaaagcacttcagccactaaccaaacattaaaagtaacgaaaaaagcaagtgtcaatggccaatcattctatttagtatcagattatgctaaaggtacaaatgttggttgggtgaaacagtcagatgtcgaatatcaaacaagtaaagccccttctaaagtgaatcaaaattatacgattaaatcgggtgcgaaattgtatcaagtgccttggggtacaagtaaacaagttgccggtacagtgacaggtgctgcgacacaaacatttaaggcaacacaatctcaaactgtaggtaaagcaacatacttgtatgggacagttggcaaattatctggttggattaattcaacagcattagcagctcaaaaaacaacaacgaatgttactaaaacaatttctcaaatcggtcaactgaacacgaaaaatagcggtgtcaaagcttctatttatgacaaaacagcaaaagatgcatccaaatgggcaggtcaaacttataaaattactaaaacagcttctgccaataacgaagactatgtattactgcaaaatagtacaggaggcacgccactcggttggttcaatgttaaagacgtcacaacacgcaacttaggtgctgaaacagctgttaaagggcggtacactgttaatagtaaaacatctggactctacgctatgccttggggtacaacgaagcaacgtgtcgatacattaaaaaatgccacaagtcgtttatttacagcttcaaaatcagttaaagtcggtaatgatacattcttattcggtacagtgaatcaaaaattgggctggattaatcaaaaagacttaacagctgtagcagcaaaagttgcaaacatgaaaactgcatcgaatagcgcagtcaaaggtgccgcaatcacaactttgaaaaaagtagaagattatgtgattacgaataaaaatggttattattacactaaagttggagattcaaaaacagctggtgctttaaaaggtttttatcaacaaatttttaaagtcgaaaaaacatctttactgaacggcattacttggtactatggcgcattccaaaacgggacgaaaggatggattaaagcagctgacatacgttcatcattcattcaacatactgcggtcagtagcacattgaaagcagcactcgataaacaaatggcgctgacttacccgcctcaagttcaacgtgtagccggtaaatgggtcaatgcgaatcgtgcagaaactgaaaaagcaatgaataccgcagcaattgaaaaagatccgactctcatttaccaatttttaaaacttgataaataccaaggtcttggcgtagaagaacttaataaattgttaagaggcaaaggcattttagaaggtcaaggtgccgcatttaaagaagccgcacaaaaacacaatattaatgaggtttacttaatgtctcacgcatttttagaaacaggtaacgggacttctcaattagccaatggcggtcacgtagataaaaataataaagtcgtaacaaacggtaaaccgaagtattacaacatgttcggtatcggggcaattgatacagacgctttacgcaatggctttaaaactgctgaaaaatatggttggaatacggtcagcaaagcgattatcggtggcgcaaaattcatccgtgatcagtacatcggttcaggacaaaacacattgtatcgtatgcgttggaatccagaacaccctgccacacatcagtatgcgactgatattaattgggcaaatgtaaacgcacaacgcatgaaatatttctatgatcaaattggtgaaacaggtaaatatttcgacgtcgatgtatataagaagtagThe protein sequence translated from SEQ ID NO 25 is designated SEQ IDNO: 26 and is shown below:

SEQ ID NO: 26 MVKKFGYKTP TIVALTLAGT AFSAHQANAA EQVAPEKTPT NVLDDQYALKQADDAKQTTQ GTTLAGSKEY KDPSQIDTTQ VDTAAQTETP VEGGQQDAQQ PTTTDEATSTDHTVSKGTNE SASPATASID EGTLNAQVNS DETATNRTQD VTENVTKYPY HSSEIDTHEDATVSPDTYHA LDTHAQQPSA MDVSDSTSAQ TEATQVNTST NVNDKEAVST TEDAPTTQLQAAVQSEANKE AKATTETAQN KTPQVEKKAT ATQNTAQLAT GHQDITDKVS KRVAVTNETKADATTAKTQA PTSVTHQADT QAKTITDKKA TTYSAQTATD QDINANPDGP TPPRVGGKGGPPASLSLQST GQTAFRSAVA SKPSAYQPKV KSSINDYIRK QNYKVPVYEE DYSSYFPKYGYRNGVGKPEG IIVHDTANDN STIDGEISYM KRNYQNAFVH GFINGQRIVE TQPTDYLAWGAGAIANERFI HIELVHVHSK EDFARQMNNM ADYAATNLQY YGLSPDSAEY DGRGTVWTHDAVSRFLGGTD HTDPHGYLKQ HGYSFDALYD LINEKYQVKM GYASPANSSS KPSTNTGLTVKNTTGFGRIN TTNSGLYTTV YDQKGKATNQ TNQTLKVTKE ATLNGNKFYL MSDAKSNQTLGWVKSNDATY QAAQAEKKVT KTYTVKPGTT VYQVPWGASS QTVGKAPGTS NQSFKSTKEQTVAKTKWLYG TVGKVTGWIN ASSVVANDQK PSTNTALKVT TDTGLGRIKD KNSGLYATVYDKTGKSTSAT NQTLKVTKKA SVNGQSFYLV SDYAKGTNVG WVKQSDVEYQ TSKAPSKVNQNYTIKSGAKL YQVPWGTSKQ VAGTVTGAAT QTFKATQSQT VGKATYLYGT VGKLSGWINSTALAAQKTTT NVTKTISQIG QLNTKNSGVK ASIYDKTAKD ASKWAGQTYK ITKTASANNEDYVLLQNSTG GTPLGWFNVK DVTTRNLGAE TAVKGRYTVN SKTSGLYAMP WGTTKQRVDTLKNATSRLFT ASKSVKVGND TFLFGTVNQK LGWINQKDLT AVAAKVANMK TASNSAVKGAAITTLKKVED YVITNKNGYY YTKVGDSKTA GALKGFYQQI FKVEKTSLLN GITWYYGAFQNGTKGWIKAA DIRSSFIQHT AVSSTLKAAL DKQMALTYPP QVQRVAGKWV NANRAETEKAMNTAAIEKDP TLIYQFLKLD KYQGLGVEEL NKLLRGKGIL EGQGAAFKEA AQKHNINEVYLMSHAFLETG NGTSQLANGG HVDKNNKVVT NGKPKYYNMF GIGAIDTDAL RNGFKTAEKYGWNTVSKAII GGAKFIRDQY IGSGQNTLYR MRWNPEHPAT HQYATDINWA NVNAQRMKYFYDQIGETGKY FDVDVYKK SEQ ID NO: 27gtgtcgacagaaaaacaagatgatacacaagcaaaagcgaatgcactttctacagatgattcaacacctacaacagaacaatcaaaaagtgataccgaaccaacgcaaaatcaagaagtgaatgaaaaagaagcaacacaagttgagcaaactccagataatgcatcatcagaatttaaagacagtgcagcacaagatgaaacaacatcgaaagacgctgacattgctcaaacaaaagaagcaaaaaatgaagcattgcaaagtgactcatcagcaaacctatcaaatcaagaagcagaaaaagaaaacacaactaacagtgaatctcaagtaaatgaacaacctaaagcagatacaacttctgattcacaagtttcaaatacacctcaacaagatcctacatcgacagtaccttcaccagaaacatcagaagacaatcgaccttcaacagaattaaaaaatagtgaaacaactgcttctcaaacaactttaaacgaacaacctactgaatcaacatccaatcaaactgaaacgacaaaagcaccaacaaatacaacagtcgcaaacaaaaaagcacctgcacaattaaaagacattaaaggtacaactcaacttcgcgcagtcagtgcaagtcaacctactgctgttgcagctggtgggacaaacgtaaatgacaaagtaacagcatcaaatatgaaaataactgaatcttatatcgagccaaacaactcaggaaacttttatttaaaaagtaactttaacgtaaacgggactgttaaagaaggtgactactttactgtaaaaatgcctgacactgtcaatacttttggtgacacgcgccattcacctgactttagagaaaaaattacaaatcaaaaaggtgaagttgtggctttaggtgaatatgatgttgccaaccatactatgacatacacgttcactaatgtcgttaataatttagaaaatgtgtccggttcgtttaacttgactcaatttatggatcgtaaagtggcaacagattctcaaacatatccattaaaatacgacattgcaggcgaatctttagatacacaaattaaagtgaattacggtcaatattacagtgaaggtgattctaacttaaaatcaatgatcacttcagaagatcctaaaactggggaatatgatcaatacatttatgtcaacccattacaaaaaacggcaaacggtacagttgtaagagttcaagggttccaagttgatccaactaagagtaatgggcaagtgaaaccagatacaacgcagatcaagattttaaaagttgctgatggtcaaccacttaatagtagtttcggtgtgaatgacagtgaatatgaagatgtcacaaaacaatttaatattgtttatcgtgataataatttggcagatatttactttggaaacttaaatgggcaacgctatatcgttaaagtgacgagcaaagaaaatttggattctaaagaggatttaaacttgcgtgctattatggccactcaaaaccgatatggtcaatataactatattacttgggataacgatattgtgaaaagctcttctggtggtacagccgacggaaatgaagcatcatatcaattaggcgacaaagtttggaatgatgtgaataaaaatggtatccaagatcaaggtgaaactggtattgctgatgtaaaggttactttaaaagatcttgatggcaacattttggatacaacttatacaaacacgaatggtaaatatatctttgataatttaaaaaatggtaattatcaagtgggttttgaaacaccggaaggctatgctgcaagtccatccaaccaaggtaatgacgcccttgactctgatggtcctacaaatgtacaagctgtcattagtgatgggaacaacttaactatcgaccaaggtttttaccaaactgaaacaccaacacacaacgtcggcgacaaagtttgggaagacttaaataaagatggcatccaagaccaaaatgaaccaggtatcgctaacgttaaggtcactttaaaagacgcggatggtaacgttgtggatacacgtacgactgatgataaagggaattacttattcgaaaaagttaaagaaggcgaatatacaattgaatttgaaacgcctgaaggttatacaccgacacaaacaggccaaggcagagtcagcactgactctaatgggacatcttcccttattttagtcgaaggtaacgatgacttaacaatcgatagcggtttctacaaagaacctgttacacacaaagttggcgacaaagtttgggatgacttaaataaagacggtatccaagatgacaatgaaccaggcatctctgacgttaaagtcactttaaaagatgcggatggtaacgtcgtagatacacgtacaactgatgctaacggtaactatttatttgaaaacgtgaaagaaggcgactatacgattgaatttgaaacgcctgaaggttacacaccgactgttacaggtcaaggtacagctgataatgactctaacggtacatctacaaaagttacagttaaagatggcgatgacttaacaattgacagtggtttcactcaagttacacctgagccaccgacacataatgttggcgacaaagtttgggatgacttaaataaagacggtatccaagatgacaatgaaccaggcatctctgacgttaaagtcactttaaaagatgcggatggtaacgtcgtagatacacgtacaactgatgctaacggtaactatttatttgaaaacgtgaaagaaggcgactatacgattgaatttgaaacgcctgaaggttacacaccgactgttacaggtcaaggtacagctgataatgactctaacggtacatctacaaaagttacagttaaagatggcgatgacttaacaattgacagtggtttcactcaagttacacctgagccaccgactgaacctgaaaaccctagtccagagcaaccttctgaaccgggtcaacctgaaaatcctagtccagagcaaccttctgaaccaggtcaacctgaaaatcctagtccagagcaaccttctgaaccaggtcaacctgaaaatcctagtccagaacaaccttctgaaccgggtcaacctgaaaatcctagtccagaacagccttctgagccaggacaacctaaaaatcctagtccagaacagccaaataatccaagtgtgccaggtgttcaaaatcctgaaaaaccaagcttaactccagtcacacaaccggttcattcaaacggcaataaagcaaaaccatctcaacaacaaaaagctttacctgaaacaggtgaaactgaatcacatcaaggtacattattcggtggtattttagctgctttaggcgcattactctttgcacgtaaaaaacgccacgataaaaaacaatcacactaaThe protein sequence translated from SEQ ID NO 27 is designated SEQ IDNO: 28 and is shown below:

SEQ ID NO: 28 VSTEKQDDTQ AKANALSTDD STPTTEQSKS DTEPTQNQEV NEKEATQVEQTPDNASSEFK DSAAQDETTS KDADIAQTKE AKNEALQSDS SANLSNQEAE KENTTNSESQVNEQPKADTT SDSQVSNTPQ QDPTSTVPSP ETSEDNRPST ELKNSETTAS QTTLNEQPTESTSNQTETTK APTNTTVANK KAPAQLKDIK GTTQLRAVSA SQPTAVAAGG TNVNDKVTASNMKITESYIE PNNSGNFYLK SNFNVNGTVK EGDYFTVKMP DTVNTFGDTR HSPDFREKITNQKGEVVALG EYDVANHTMT YTFTNVVNNL ENVSGSFNLT QFMDRKVATD SQTYPLKYDIAGESLDTQIK VNYGQYYSEG DSNLKSMITS EDPKTGEYDQ YIYVNPLQKT ANGTVVRVQGFQVDPTKSNG QVKPDTTQIK ILKVADGQPL NSSFGVNDSE YEDVTKQFNI VYRDNNLADIYFGNLNGQRY IVKVTSKENL DSKEDLNLRA IMATQNRYGQ YNYITWDNDI VKSSSGGTADGNEASYQLGD KVWNDVNKNG IQDQGETGIA DVKVTLKDLD GNILDTTYTN TNGKYIFDNLKNGNYQVGFE TPEGYAASPS NQGNDALDSD GPTNVQAVIS DGNNLTIDQG FYQTETPTHNVGDKVWEDLN KDGIQDQNEP GIANVKVTLK DADGNVVDTR TTDDKGNYLF EKVKEGEYTIEFETPEGYTP TQTGQGRVST DSNGTSSLIL VEGNDDLTID SGFYKEPVTH KVGDKVWDDLNKDGIQDDNE PGISDVKVTL KDADGNVVDT RTTDANGNYL FENVKEGDYT IEFETPEGYTPTVTGQGTAD NDSNGTSTKV TVKDGDDLTI DSGFTQVTPE PPTHNVGDKV WDDLNKDGIQDDNEPGISDV KVTLKDADGN VVDTRTTDAN GNYLFENVKE GDYTIEFETP EGYTPTVTGQGTADNDSNGT STKVTVKDGD DLTIDSGFTQ VTPEPPTEPE NPSPEQPSEP GQPENPSPEQPSEPGQPENP SPEQPSEPGQ PENPSPEQPS EPGQPENPSP EQPSEPGQPK NPSPEQPNNPSVPGVQNPEK PSLTPVTQPV HSNGNKAKPS QQQKALPETG ETESHQGTLF GGILAALGALLFARKKRHDK KQSH SEQ ID NO: 29atgaagaaaacaatttcagtacttggtctagggctattagcaacattttttgtaagtaacgaatcatatgccgcagaaacgattcaaaacaatacgtcatcaagtgaaacgaatcaaaattcagatcagacgccgttagatcattatattcgaaaagcagatggcacactggttgaaccgaacgtgtacccacataaagattatgtagagaatgaaggacctttaccagagtttaaatttcaagttgactctaagaaagattcatctgatccaaatcaagcaccgttagatcattatattcgaaaagcggatggcacgttggttgaaccgaatgtatatccacacaaagattatgtcgaaaatgaagggcctttaccagagtttaaatttatgtatgctgacaaacaaaatcatcatgaccaacagagtaaaaacaacaaggataagcagcgtgcaaattacagtgacaaaaagcataatgatcagccgggtcatccaaaagcagtcacgccagctgtacaacatgataaagcagtcacttcaaacgctactgtaaaagcattgccaaacacaggtgaatctgataaaacaacacaattaccaatcgtattatcattgttatctgtggggattttagttttattaaaattgagaaaataaThe protein sequence translated from SEQ ID NO 29 is designated SEQ IDNO: 30 and is shown below:

SEQ ID NO: 30 MKKTISVLGL GLLATFFVSN ESYAAETIQN NTSSSETNQN SDQTPLDHYIRKADGTLVEP NVYPHKDYVE NEGPLPEFKF QVDSKKDSSD PNQAPLDHYI RKADGTLVEPNVYPHKDYVE NEGPLPEFKF MYADKQNHHD QQSKNNKDKQ RANYSDKKHN DQPGHPKAVTPAVQHDKAVT SNATVKALPN TGESDKTTQL PIVLSLLSVG ILVLLKLRK SEQ ID NO: 31atgaaaagtaaatatgattttttacctaatagacttaataaattttctatacgaaaatttactgttggtagtgtatcagtgctaataggagccactttattattcgggtttgtagaaggagaagcatcagcatcagtaaaagaaggtcaacaaagtataaattctagtgagaaagaaagcgccgatcctacagtagttgatttaattagtaagaaagaaacaaatttagatggactagatgtatcaagagaagaaacgaccaaagtaccaataaatgaaaacaaaagaggtgaggaacaaagtatttctgataaagctataacagaaaaagctgatacaccagtaagcaatttatcaagtaaggaagttgaggagcaaggtgtttctgataaagctataacagaaaaagctgatacaccagtaaccaatttatcaagtaaggaagctaaggagcaaggtgcttctgatagagttataacagaaaaagctgatacaccagtaagcaatttatcaagtaaggaagctaaggagcaaggtgcttctgatagagttataacagaaaaagctgatacaccagtaagcaatttatcaagtaaggaagttgaggagcaaggtgtttctgataaagctatagagaaaatagctgatgcatcagctactgatttgtcaagtaaggaagaagtagaacaagatatatctacacaaggtaaagtaaaatcaaaggaagcagtacaagtagaaagtagtcagttacaaaatttaaatagtgaaataaatgctgaacctaatgaaattaaggcaatagatagaagttcaatattacctttaaatttaaatgatgaagaaaataacaaaaaagttaataaagggactcgggttccagaagctacattaagaaatgcctctaataaccaactcaatacacgaatgagatcagtgagtttatttagagttgctagactaacagaaatcaatagaaatgttaatgataaagtaaaggtttcggatatcgacatcgcaatagccccaccgcatactaaccctaaaactggaaaagaagaattttgggcgacatcttcttcagttttaaagttaaaggcaagctatgaattggataatagcatttctaaaggggatcaatttactattcaatttggtcaaaatattcgtccaggtggattaaatttaccaagaccttataattttttatatgataaggataaaaaattagttgcaactggccgttacaataaagaatcaaatacaatcacatatacatttacggattatgtagataaacatcaaaacattaaaggtagttttgagatgaatgcattttctagaaaggaaaatgctactactgacaaaacagcatatccaatggatgttactattgcgaatcaaaaatatagtgaaaatattattgtagactatggtaataaaaagaatgctgctattatttcaagtacagaatatattgatttagatggtagtagaaaaatgacaacatatattaatcaaaatggtagtaaaaattccatctatcgtgctgatatgcaaattgatttgaacggttataaatttgatccatccaaaaacaattttaaaatttatgaagtggaaaatagcagtgactttgtggatagcttttcaccagatgtgagcaagttaagggatgttacgagtcaatttaatattcaatatacaaataataatacaatggcaaaagtggattttggtactaacctttggaggggtaaaaaatatattattcagcaagtggcgaatatagacgacagtaaattagtgaaaaatgcttcaatcaattatacattgaataaaatggattttaataataaaagaacggtagaaacacataacaatacttattctacagtgaaagataaatcaacagcactaggtgacgtacaggaaagtcaatctattagtgagagccaatcagttagtgaaagcgagtcactaagtgagagccaatcaatcagtgaaagcgaatcattaagtgagagccaatcaatcagtgaaagcgaatcattaagtgaaagtcaatcaatctcagagagcgaatcactaagtgaaagtcagtcaatttcagaaagcgaatcattaagtgaaagccaatcaatctcagagagtgaatcattaagtgaaagtcagtcaatttcagagagtgaatcactaagtgaaagtcagtcaatttcagaaagcgaatcattaagcgagagtcagtcaatttcagaaagcgaatcattaagcgagagtcagtcaatttcagaaagcgaatcattaagtgaaagccaatcaatcagtgaaagcgaatcactaagcgagagccaatcaatctcagagagtgaatcattaagcgagagtcaatcaatctcagagagcgaatcattaagtgagagtcaatcaatcagtgaaagcgagtcactaagtgagagtcaatcaatttcagagagcgaatcattaagtgaaagccaatcaatctcagagagtgaatcactaagtgagagccaatcaatctcagagagtgaatcattaagtgagagccaatcaatctcagagagcgagtcactaagcgagagccaatcaatttcagagagtgaatcactaagtgaaagtcaatcaatttcagagagcgaatcactaagtgagagccaatcaatctcagagagcgaatcactaagtgaaagtcaatcaatttcagagagtgaatcactaagcgagagccaatcaatctcagagagtgaatcattaagtgaaagtcagtcaatttcagagagtgaatcactaagtgaaagtcagtcaatttcagaaagcgaatcattaagtgaaagccaatcaatcagtgaaagcgaatcactaagcgagagtcaatcaatctcagagagcgaatcattaagtgaaagtcaatcaatttcagaaagcgagtcattaagcgagagtcagtcaatctcagagagcgaatcactaagcgagagtcaatcaatctcagagagtgaatcattaagtgagagccaatcagttagtgaaagcgaatcactaagtgaaagtcagtcaatttcagaaagcgaatcattaagtgagagtcaatcaatttcagaaagcgaatcattaagtgaaagccaatcaatcagtgaaagcgaatcactaagcgagagccaatcaatcagtgaaagcgaatcattaagtgagagtcaatcaatctcagaaagcgaatcattaagtgagagtcaatcaatcagtgaaagcgaatcactaagcgagagccaatcaatctcagagagcgaatcactaagcgagagccaatcaatctcagagagcgagtcactaagcgagagccaatcaatcagtgaaagcgaatcattaagtgagagtcaatcaatcagtgaaagcgagtcactaagtgagagccaatcaatctcagagagtgaatcattgagtgagagccaatcaatctcagagagcgagtcactaagtgagagtcaatcaatttcagagagcgaatcattaagtgaaagccaatcaatctcagagagtgaatcattgagtgagagccaatcagttagtgaaagcgagtcactaagtgagagtcaatcaatcagtgaaagcgagtcactaagtgagagtcaatcaatttcagagagcgaatcattaagcgagagtcagtcaatctcagagagtgaatcactaagtgagagccaatcaatctcagagagtgaatcattaagtgagagccaatcaatctcagagagtgaatcactaagtgagagtcaatcaatcagtgaaagcgaatcactaagcgagagccaatcaatttcagagagtgaatcattaagtgagagccaatcagttagtgaaagcgaatcactaagcgagagccaatcaatctcagagagcgaatcattgagtgagagccaatcaatctcagagagtgaatcattgagtgagagtcaatcaatcagtgaaagcgaatcactaagcgaaagtcaatcaatttcagagagtgaatcattgagtgagagccaatcaatttcagagagtgaatcactaagtgaaagtcagtcaatttcagaaagcgaatcactaagcgagagccaatcaatctcagagagcgaatcactaagtgaaagtcagtcaatttcagaaagcgaatcattaagtgaaagccaatcaatctcagagagtgaatcattaagtgaaagtcagtcaatttcagagagtgaatcactaagtgaaagtcagtcaatttcagaaagcgaatcattaagcgagagtcagtcaatttcagaaagcgaatcattaagtgaaagccaatcaatcagtgaaagcgaatcactaagcgagagccaatcaatctcagagagcgaatcactaagcgagagccaatcaatctcagagagcgaatcactaagtgaaagtcaatcaatttcagagagtgaatcattgagtgagagtcaatcaatttcagagagtgaatcactaagtgaaagtcaatcaatttcagagagtgaatcactaagcgagagccaatcaatctcagagagtgaatcattaagtgaaagtcagtcaatttcagagagggaatcactaagtgaaagtcagtcaatttcagaaagcgaatcattaagtgaaagccaatcaatcagtgaaagcgaatcactaagtgaaagtcaatcaatctcagagagtgaatcactaagtgagagccaatcaatctcagagagtgaatcattgagtgagagccaatcaatctcagagagcgaatcactaagtgaaagtcaatcaatttcagaaagcgagtcattaagcgagagtcagtcaatctcagagagtgaatcactaagtgagagccaatcaatctcagagagtgaatcactaagtgagagtcaatcaatcagtgaaagcgaatcactaagcgagagccaatcaatttcagagagtgaatcattaagtgagagccaatcagttagtgaaagcgaatcactaagcgagagccaatcaatctcagagagcgagtcactaagcgagagtcaatcaatctcagagagtgaatcactaagtgaaagtcagtcaatttcagaaagcgagtcactaagcgagagtcaatcaatctcagagagtgaatcattgagtgagagccaatcaatctcagagagcgaatcattgagtgagagccaatcaatctcagagagtgaatcattgagtgagagccaatcaatttcagagagcgaatcactaagcgagagccaatcaatcagtgaaagcgaatcattaagtgagagtcagtcaattagcgaaagcgaatcactaagtgagagtcaatcaatctcagagagtgaatcactaagtgaaagtcagtcaatcagcgaaagcgaatctaaatctttacctaataccggtactggagaaaagatttctaattatccaggtattttaggaggattattaagcatattaggtataagtttgcttaaaagaaaagacagagagaaaaaattaggacaaaaatctaataagtagThe protein sequence translated from SEQ ID NO 31 is designated SEQ IDNO: 32 and is shown below:

SEQ ID NO: 32 MKSKYDFLPN RLNKFSIRKF TVGSVSVLIG ATLLFGFVEG EASASVKEGQQSINSSEKES ADPTVVDLIS KKETNLDGLD VSREETTKVP INENKRGEEQ SISDKAITEKADTPVSNLSS KEVEEQGVSD KAITEKADTP VTNLSSKEAK EQGASDRVIT EKADTPVSNLSSKEAKEQGA SDRVITEKAD TPVSNLSSKE VEEQGVSDKA IEKIADASAT DLSSKEEVEQDISTQGKVKS KEAVQVESSQ LQNLNSEINA EPNEIKAIDR SSILPLNLND EENNKKVNKGTRVPEATLRN ASNNQLNTRM RSVSLFRVAR LTEINRNVND KVKVSDIDIA IAPPHTNPKTGKEEFWATSS SVLKLKASYE LDNSISKGDQ FTIQFGQNIR PGGLNLPRPY NFLYDKDKKLVATGRYNKES NTITYTFTDY VDKHQNIKGS FEMNAFSRKE NATTDKTAYP MDVTIANQKYSENIIVDYGN KKNAAIISST EYIDLDGSRK MTTYINQNGS KNSIYRADMQ IDLNGYKFDPSKNNFKIYEV ENSSDFVDSF SPDVSKLRDV TSQFNIQYTN NNTMAKVDFG TNLWRGKKYIIQQVANIDDS KLVKNASINY TLNKMDFNNK RTVETHNNTY STVKDKSTAL GDVQESQSISESQSVSESES LSESQSISES ESLSESQSIS ESESLSESQS ISESESLSES QSISESESLSESQSISESES LSESQSISES ESLSESQSIS ESESLSESQS ISESESLSES QSISESESLSESQSISESES LSESQSISES ESLSESQSIS ESESLSESQS ISESESLSES QSISESESLSESQSISESES LSESQSISES ESLSESQSIS ESESLSESQS ISESESLSES QSISESESLSESQSISESES LSESQSISES ESLSESQSIS ESESLSESQS ISESESLSES QSISESESLSESQSISESES LSESQSISES ESLSESQSIS ESESLSESQS ISESESLSES QSISESESLSESQSVSESES LSESQSISES ESLSESQSIS ESESLSESQS ISESESLSES QSISESESLSESQSISESES LSESQSISES ESLSESQSIS ESESLSESQS ISESESLSES QSISESESLSESQSISESES LSESQSISES ESLSESQSIS ESESLSESQS ISESESLSES QSISESESLSESQSVSESES LSESQSISES ESLSESQSIS ESESLSESQS ISESESLSES QSISESESLSESQSISESES LSESQSISES ESLSESQSIS ESESLSESQS VSESESLSES QSISESESLSESQSISESES LSESQSISES ESLSESQSIS ESESLSESQS ISESESLSES QSISESESLSESQSISESES LSESQSISES ESLSESQSIS ESESLSESQS ISESESLSES QSISESESLSESQSISESES LSESQSISES ESLSESQSIS ESESLSESQS ISESESLSES QSISESESLSESQSISESES LSESQSISES ESLSESQSIS ESESLSESQS ISERESLSES QSISESESLSESQSISESES LSESQSISES ESLSESQSIS ESESLSESQS ISESESLSES QSISESESLSESQSISESES LSESQSISES ESLSESQSIS ESESLSESQS ISESESLSES QSVSESESLSESQSISESES LSESQSISES ESLSESQSIS ESESLSESQS ISESESLSES QSISESESLSESQSISESES LSESQSISES ESLSESQSIS ESESLSESQS ISESESLSES QSISESESLSESQSISESES KSLPNTGTGE KISNYPGILG GLLSILGISL LKRKDREKKL GQKSNK SEQ ID NO:33 atgttaagaacaaattataaactaagaaagcttaaagtaggtttagtatcgacaggtgtggcgttgacttttgtgatggcaagtgggaatgcagaggcgtcggagaacgagcagactgaagtaaaaggggaggcgcaagttgcttctgtgaatgaaaaagagagtgaagcagaattacctgtagcgcaacaagaagcatctattcaactagacaaagtacaaccaggcgatgcacagctttcaggctatacacagccaaacaaagcgatttctgtaaagatcgacaataaagatattgtgtctgtagatgatggctatgaagaggtattatcggatgatacaggtaaatttgtatatgatttgaaagggcgtcaaattgtttacaatcaaaaagttgatgttgaagcgatgacgccatttaattttgaagattttgatgaatcagcacttgagagcgaagaggcattggaggcgttaggtcaattggaagacgaagaaacagcgacagcttctgtgacgacgcctagatatgaaggtgcgtatacagttcctgaagaacgcttgacacccattcaaggccaacagcaagtattcatcgaacctattttagaaggggcaagtaaaatcaaaggacatacatctgtacaaggtaaagtcgcgttagcaatcaatcaagaacatgtgcacctaggtgatacgttagaagaacaagcagcactcactgatcaagagtggcaaggtcgttatgacgggatttggcgccatattgatgatcaagggtttttcgagtttgacttgaaccgtctttacaataaatcttacccattgaagtctggcgatttagtgactttatcttttaaatctaatgacgaagtaggcccattattcaatgtgaacgttgagcctttcgaacgtgtggcacaagctaaaacaaagtatgagcagaatgacagtccagtagtcaacaaattggatgatactaaaagtgacttggaggttcaacctatctatggagaccttacacaagcagcagtacatggcgagtcgaaagtgttgataccggggacgtcaaaagttgaaggacgtacgaattatgcacatgcatggatagagatggcatctaatttaggggaatatcgtagtttccctaaattacaagctgatgcgacaggtgcgtttatatttgatttaaaagcggcagacatacaattgttaaacggagaacgtttgacattcagagccgttgacccacatacaaaacaacagttagctgaaactacatcagaagtacgcccagtagatatgcaagatgaagagtcagaggttgtgcagacttcaagcactgagaaatcagcacttgcggatgaaattcttcgttctatgacaattgacaaatcatttaatcctgaagttaccgagataccgggtcatgtatatcctaagaaaacagaggataaaggtgctgaaaatacagaacaagcctcagagaattctgagaagccatctcagactacagaatctcaaaatgatgccgtacaagatgtagagaaatcctctgttaatgaggaggttacgccaccttcaacagaatctgctcaagttgaaaaggggcaaaatacagaaggggctttgcttccaaaaaatgtagaacaacatgtagagagtataccataccaaaaacgtaaagcgttgataggactgacaaaacatcaaggatcagggcacatgccgccattttctttaagctttaataataaagaagatgacgtatccacaaaggttaacgaagcaaacgagcatgaacgtaagcagggtacagtttatccagagcaaatagaacaattacctcaaacaggtttaactgaaaaatcgccattctgggcattgttatttgttgtatcaggcacaggtttattattattcaaacgttctagacgacaacgccaatcttaaThe protein sequence translated from SEQ ID NO 33 is designated SEQ IDNO: 34 and is shown below:

SEQ ID NO: 34 MLRTNYKLRKLKVGLVSTGVALTFVMASGNAEASENEQTEVKGEAQVASVNEKESEAELPVAQQEASIQLDKVQPGDAQLSGYTQPNKAISVKIDNKDIVSVDDGYEEVLSDDTGKFVYDLKGRQIVYNQKVDVEAMTPFNFEDFDESALESEEALEALGQLEDEETATASVTTPRYEGAYTVPEERLTPIQGQQQVFIEPILEGASKIKGHTSVQGKVALAINQEHVHLGDTLEEQAALTDQEWQGRYDGIWRHIDDQGFFEFDLNRLYNKSYPLKSGDLVTLSFKSNDEVGPLFNVNVEPFERVAQAKTKYEQNDSPVVNKLDDTKSDLEVQPIYGDLTQAAVHGESKVLIPGTSKVEGRTNYAHAWIEMASNLGEYRSFPKLQADATGAFIFDLKAADIQLLNGERLTFRAVDPHTKQQLAETTSEVRPVDMQDEESEVVQTSSTEKSALADEILRSMTIDKSFNPEVTEIPGHVYPKKTEDKGAENTEQASENSEKPSQTTESQNDAVQDVEKSSVNEEVTPPSTESAQVEKGQNTEGALLPKNVEQHVESIPYQKRKALIGLTKHQGSGHMPPFSLSFNNKEDDVSTKVNEANEHERKQGTVYPEQIEQLPQTGLTEKSPFWALLFVVSGTGLLLFKRSRRQRQS SEQ ID NO: 35atgaaaactaaatacacagcaaaattattaattggggcagcaacaatatctttagcaacatttatttcacaagggaacgcacatgcgagcgaacaaactacaggactcgcaccggcacaacctgtcaactttgattcaatcaatgtaacgccagaccaaaaaacattctatcaagtcttacatatggaaggcatttcagaagaccaacgtgaacaatatttgaaacaattgcacgaagacccaagtagcgcacaaaatgttttttcagaatcaattaaagatgccatccacccggaacgtcgtgttgcgcaacaaaatgcgttttacagcgtattacacaacgatgacttatccgaagagcaacgtgatgcatacattggtagaattaaagaagatccagatcaaagccaagaagtatttgttgagtctttaaatgtggcacctaaagcagaatcacatgaagatcgcctcattgaattacaaaacaaaaatttaatggaagcgaatgaagcacttaaagcgttacaacaagaagacagcattcagaatagacgtgcggctcaacgtgctgtcaacaaattgacgccggatagcgcgaacgcattccaaaaagaattagatcaaatcaatgccccacgcgacgctaaaattaaagctgacgctgaagcaaaaaaacaagcacctgaagtaagcgcaccacaaattgaagatgcacctactactgaagttgcaccatctccaaaacaagatatgccaaaagtagataaaaaagaagaagataaagtagaaagtgatactgaggtcaaagaagtacctaaagctgatacagagaaaaaccctcaatctaaagacacttctaaaactgaacaagctaaagaaacacctaaagtagagcaatcacctaaaacagaaaaggctgaagaagcacctaaagcagaaacacctcaaaatggaaataaagcacaaactgaagaagctaaaccagaagtaaaagacaatgtgaaaaacactccatctgcacctgtgttacctgaaacaggaaaagcaacaacttcaacacttgaaagctactggaattctttcaaagacagtgtgaataaaggttatacttacattaaacaaagcttagaaagtggttatcaatatttaaaaggtcaatacgactatatcactaaaaaatacaatgatgcgaaatactatacaaaaatgtattcaaatcataagtctacaattgatcagtctgtattagctatattaggtaaaactggatctagcgcatatatcaagccattaaatatcgaagaaaattcaaacgtattttacaaagcttatgcaaaaacaagaaactttgctacagaaagcattaacacaggaaaagtattatacacattatatcaaaaccctactgtagttaaatctgctttcactgcaattgaaacagcaaatacagtaaaaaatgcaataagcaatcttttctctctcttcaaataaThe protein sequence translated from SEQ ID NO 35 is designated SEQ IDNO: 36 and is shown below:

SEQ ID NO: 36 MKTKYTAKLLIGAATISLATFISQGNAHASEQTTGLAPAQPVNFDSINVTPDQKTFYQVLHMEGISEDQREQYLKQLHEDPSSAQNVFSESIKDAIHPERRVAQQNAFYSVLHNDDLSEEQRDAYIGRIKEDPDQSQEVFVESLNVAPKAESHEDRLIELQNKNLMEANEALKALQQEDSIQNRRAAQRAVNKLTPDSANAFQKELDQINAPRDAKIKADAEAKKQAPEVSAPQIEDAPTTEVAPSPKQDMPKVDKKEEDKVESDTEVKEVPKADTEKNPQSKDTSKTEQAKETPKVEQSPKTEKAEEAPKAETPQNGNKAQTEEAKPEVKDNVKNTPSAPVLPETGKATTSTLESYWNSFKDSVNKGYTYIKQSLESGYQYLKGQYDYITKKYNDAKYYTKMYSNHKSTIDQSVLAILGKTGSSAYIKPLNIEENSNVFYKAYAKTRNFATESINTGKVLYTLYQNPTVVKSAFTAIETANTVKNAISNLFSLFKAn active domain from the protein of SEQ ID NO: 6 is designated SEQ IDNO: 37

SEQ ID NO: 37 NEDVTETTGRNSVTTQASEQHLQVEAVPQEGNNVNVSSVKVPTNTATQAQEDVASVSDVKAHADDALQVQESSHTDGVSSEFKQETAYANPQTAETVKPNSEAVHQSEYEDKQKPVSSSRKEDETMLQQQQVEAKNVVSAEEVSKEENTQVMQSPQDVEQHVGGKDISNEVVVDRSDIKGFNSETTIRPHQGQGGRLNYQLKFPSNVKPGDQFTIKLSDNINTHGVSVERTAPRIMAKNTEGATDVIAEGLVLEDGKTIVYTFKDYVNGKQNLTAELSVSYFVSPEKVLTTGTQTFTTMIGNHSTQSNIDVYYDNSHYVDGRISQVNKKEAKFQQIAYINPNGYLNGRGTIAVNGEVVSGTTKDLMQPTVRVYQYKGQGVPPESITIDPNMWEEISINDTMVRKYDGGYSLNLDTSKNQKYAIYYEGAYDAQADTLLYRTYIQSLNSYYPFSYQKMNGVKFYENSASGSGELKPKPPEQPKPEPEIQADVVDIIEDSHVI DIGWAn spsl gene fragment corresponding to A domain is designated SEQ ID NO:38, which encodes the protein of SEQ ID NO: 37

SEQ ID NO: 38 AATGAAGATGTCACTGAAACAACTGGGAGAAATTCAGTGACAACGCAAGCTTCTGAGCAACATTTGCAAGTGGAAGCAGTACCTCAAGAAGGCAATAATGTAAATGTATCCTCTGTAAAAGTACCTACGAATACGGCAACGCAAGCACAAGAAGATGTTGCAAGTGTATCCGATGTTAAAGCACATGCTGATGATGCATTACAAGTACAAGAAAGTAGTCATACTGATGGTGTTTCTTCAGAATTCAAGCAGGAGACAGCTTATGCGAATCCTCAAACAGCTGAGACAGTTAAACCTAATAGTGAAGCAGTGCATCAGTCTGAATACGAGGATAAGCAAAAACCCGTATCATCTAGCCGCAAAGAAGATGAGACTATGCTTCAGCAGCAACAAGTTGAAGCCAAAAATGTTGTGAGTGCGGAGGAAGTGTCTAAAGAAGAAAATACTCAAGTGATGCAATCCCCTCAAGACGTTGAACAACATGTAGGTGGTAAAGATATCTCTAATGAGGTTGTAGTGGATAGGAGTGATATCAAAGGATTTAACAGCGAAACTACTATTCGACCTCATCAGGGACAAGGTGGTAGGTTGAATTATCAATTAAAGTTTCCTAGCAATGTAAAGCCAGGCGATCAGTTTACTATAAAATTATCTGACAATATCAATACACATGGTGTTTCTGTTGAAAGAACCGCACCGAGAATCATGGCTAAAAATACTGAAGGTGCGACGGATGTAATTGCTGAAGGTCTAGTGTTGGAAGATGGTAAAACCATCGTATATACATTTAAAGACTATGTAAATGGCAAGCAAAATTTGACTGCTGAGTTATCAGTGAGCTATTTCGTAAGTCCGGAAAAAGTCTTGACTACTGGGACACAAACATTCACGACGATGATCGGTAATCATTCAACGCAATCCAATATTGACGTTTATTATGATAATAGTCATTATGTAGATGGACGTATTTCGCAAGTGAACAAAAAAGAAGCTAAATTTCAACAAATAGCATACATTAACCCTAATGGCTATTTAAATGGCAGGGGGACAATTGCAGTTAATGGTGAAGTGGTCAGTGGTACGACTAAAGACTTAATGCAACCTACAGTGCGTGTATATCAATATAAAGGACAAGGTGTTCCTCCTGAAAGTATTACTATAGACCCTAATATGTGGGAAGAAATCAGCATAAACGATACTATGGTAAGAAAATATGATGGTGGCTATAGCTTGAATCTGGATACCAGCAAGAATCAAAAATATGCCATCTATTATGAAGGGGCATATGATGCGCAAGCTGACACACTGTTGTATAGAACATATATACAGTCATTAAACAGTTACTATCCGTTCAGTTACCAAAAAATGAACGGTGTGAAGTTTTACGAAAACAGTGCGAGTGGAAGCGGTGAGTTGAAACCGAAACCACCTGAACAACCAAAACCAGAACCTGAAATTCAAGCTGATGTAGTAGATATTATTGAAGATAGCCATGTGATT GATATAGGATGG

Since each of the abovementioned proteins/nucleic acid sequences isderived from Staphylococcus pseudintermedius, the inventors havedesignated these (and the corresponding protein sequences)Staphylococcus pseudintermedius surface genes/nucleic acids/proteins(Sps). For simplicity, the bulk of this specification will use the term“Sps” or “Sps genes” or “Sps nucleic acids” which are intended toencompass all of the nucleic acid sequences described above (i.e. SEQ IDNOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33 and35.

Furthermore, in addition to encompassing the entire or completegene/nucleic sequences listed above, it is to be understood that thedesignation “Sps” also encompasses fragments, portions, mutants,derivatives and/or homologoues/orthologues of any of these genes.

In addition, the term “Sps” or “Sps proteins” encompasses theproteinaceous products of the Sps genes/nucleic acids or fragments,portions, analogues, variants or derivatives thereof (for example shortpeptide fragments). In particular, the term “Sps proteins” encompassesthe sequences given as SEQ ID NOS: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20,22, 24, 26, 28, 30, 32, 34, 36 and 37 above.

Typically, the gene/nucleic acid fragments, portions, mutants, variants,derivatives and/or homologues/orthologues of the invention arefunctional or active—that is, they retain the function and/or activityof the wild type or native Sps genes/nucleic acids. Advantageously,fragments, portions, mutants, variants, derivatives and/orhomologues/orthologues of any of the Sps genes/nucleic acids provided bythis invention, encode proteins (or peptides, peptide fragments)retaining the ability to bind to or associate with extracellular matrixproteins such as, for example, fibrinogen, fibronectin and/or collagen.In other embodiments, the proteins and/or peptides encoded by thenucleic acid sequences described herein are immunogenic or antigenic.Furthermore, fragments, portions, variants or derivatives of any of theproteins encoded by the nucleic acid sequences described herein may alsoretain the immunogenicity and/or antigenicity of a corresponding wildtype Sps protein (for example the proteins listed above). Where theinvention relates to immunogenic compositions and/or vaccines, the useof proteins and/or peptides which are immunogenic (or antigenic) isimportant.

The term “mutants” may encompass naturally occurring mutants or thoseartificially created by the introduction of one or more nucleic acidadditions, deletions, substitutions or inversions.

Homologous or identical genes, nucleic acid or protein sequences mayexhibit as little as approximately 20 or 30% sequence homology oridentity to certain reference sequences, however, in other cases,homologous or identical genes/nucleic acids and/or proteins may exhibitat least 40, 50, 60, 65, 70, 75, 80, 85, 90, 91, 92, 93, 94, 95, 96, 97,98, 99% homology or identity to the various sequences given above as SEQID NOS: 1-36 or 37-38. It should be understood that mutant, variant,derivative and/or orthologuous sequences may exhibit similar levels ofhomology/identity to each other and/or to the Sps genes/nucleic acidsshown as SEQ ID NOS 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27,29, 31, 33, 35 and/or 38 above.

One of skill in this field will readily understand that genes/nucleicacids homologous/identical to the Sps genes detailed herein may be foundin other bacterial species. As such, homologous genes from other speciesmay be included within the scope of this invention. Using the variousnucleic acid and amino acid sequences described herein, one of skill inthe art could readily identify related sequences in other microbial(particularly bacterial) species. For example, nucleic acid obtainedfrom a particular bacterial species may be probed using the probesderived from the sequences of this invention, to identify homologous orclosely related sequences.

It should be understood that Sps nucleic acid sequences of thisinvention may be single-stranded or double-stranded and asingle-stranded nucleic acid molecule may include a polynucleotidefragment having a nucleotide sequence that is complementary to anucleotide sequence that encodes a Sps protein or fragment thereof. Asused herein, the term “complementary” refers to the ability of twosingle stranded polynucleotide fragments to base pair with each other.

A single-stranded nucleic acid molecule of the invention may furtherinclude a polynucleotide fragment having a nucleotide sequence that issubstantially complementary to a nucleotide sequence that encodes a Spsprotein or fragment thereof according to the invention, or to thecomplement of the nucleotide sequence that encodes said Sps protein orfragment thereof. Substantially complementary polynucleotide fragmentscan include at least one base pair mismatch, such that at least onenucleotide present on a first polynucleotide fragment will not base pairto at least one nucleotide present on a second polynucleotide fragment,however the two polynucleotide fragments will still have the capacity tohybridize. The present invention therefore encompasses polynucleotidefragments which are substantially complementary. Two polynucleotidefragments are substantially complementary if they hybridize underhybridization conditions exemplified by 2×SSC (SSC: 150 mM NaCl, 15 mMtrisodium citrate, pH 7.6) at 55° C. Substantially complementarypolynucleotide fragments for purposes of the present invention maypreferably share at least about 60, 65, 70, 75, 80 or 85% nucleotideidentity, preferably at least about 90%, 95% or 99% nucleotide identity.Locations and levels of nucleotide sequence identity between twonucleotide sequences can be readily determined using, for example,CLUSTALW multiple sequence alignment software.

In addition, it should be understood that the present invention alsorelates to the products of the genes/nucleic acids encompassed by thisinvention and in particular to proteins or peptides homologous/identicalto those having sequences provided by SEQ ID NOS: 2, 4, 6, 8, 10, 12,14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36 and 37. Furthermore,fragments, portions, analogues, variants, derivatives of any of these orhomologous and/or identical or modified proteins are also within thescope of this invention. Typically, fragments, portions, derivatives,variants and/or homologous or modified proteins or peptides of theinvention are functional or active—that is they retain the function of awild type Sps protein. In certain embodiments fragments, portions,derivatives or variants of, and/or modified sequences or sequences withhomology or identity to, the amino acid sequences provided by thisinvention, retain the ability to bind to or associate with extracellularmatrix proteins such as, for example, fibrinogen, fibronectin and/orcollagen.

Additionally or alternatively, fragments, portions, mutants, variants,derivatives and/or homologues/orthologues of the Sps genes provided bythis invention, may encode proteins (or peptide fragments) that areantigenically similar or identical to the proteins encoded by the genesdescribed herein. Similarly, fragments, portions, derivatives and/orvariants of and/or modified sequences or sequences with homology oridentity to, the amino acid sequences provided by this invention arealso antigenically similar or identical to the proteins encoded by thegenes described herein. It should be understood that the term“antigenically similar or identical” may encompass proteins or peptideseliciting an immune response similar or identical to the immune responseelicited by any of the Sps proteins described herein. In certainembodiments fragments, portions, derivatives and/or variants of and/ormodified sequences or sequences with homology or identity to, the aminoacid sequences described herein, elicit immune responses which protectagainst Staphylococcus pseudintermedius infection and/or prevent, reduceor neutralise Staphylococcus pseudintermedius cell/tissue adhesionand/or colonisation. One of skill will readily understand that theantigenicity of a polypeptide can be evaluated in vitro by, for example,performing a Western blot on the purified polypeptide (for example, anaffinity purified polypeptide) using polyclonal antisera from an animal,such as a rabbit that was vaccinated with at least an antigenic portionof an Sps protein of the present invention.

One of skill in this field will readily understand that for the variousnucleic acid sequences and polypeptides described herein, naturalvariations due to, for example, polymorphisms, may exist between Spsgenes and proteins isolated from different microbial species and evendifferent strains of the same species. Gene or protein variants maymanifest as proteins and/or genes that exhibit one or more aminoacid/nucleic acid substitutions, additions, deletions and/or inversionsrelative to a reference sequence (for example any of the sequencesdescribed above). As such, it is to be understood that all such naturalvariants, especially those that are functional or display the desiredactivity, are to be included within the scope of this invention.

In another embodiment, the invention relates to derivatives of any ofthe Sps sequences described herein. The term “derivatives” may encompassSps genes or peptide sequences which, relative to those describedherein, comprise one or more amino acid substitutions, deletions,additions and/or inversions.

Additionally, or alternatively, analogues of the various peptidesdescribed herein may be produced by introducing one or more conservativeamino acid substitutions into the primary sequence. One of skill in thisfield will understand that the term “conservative substitution” isintended to embrace the act of replacing one or more amino acids of aprotein or peptide with an alternate amino acid with similar propertiesand which does not substantially alter the physcio-chemical propertiesand/or structure or function of the native (or wild type) protein.Analogues of this type are also encompassed with the scope of thisinvention. In one embodiment, substitute amino acids may be selectedfrom other members of the class to which the amino acid belongs. Forexample, nonpolar (hydrophobic) amino acids include alanine, leucine,isoleucine, valine, praline, phenylalanine, tryptophan, and tyrosine.Polar neutral amino acids include glycine, serine, threonine, cysteine,tyrosine, asparagine and glutamine. The positively charged (basic) aminoacids include arginine, lysine and histidine. The negatively charged(acidic) amino acids include aspartic acid and glutamic acid. Examplesof preferred conservative substitutions include Lys for Arg and viceversa to maintain a positive charge; Glu for Asp and vice versa tomaintain a negative charge; Ser for Thr so that a free —OH ismaintained; and Gln for Asn to maintain a free NH₂.

As is well known in the art, the degeneracy of the genetic code permitssubstitution of one or more bases in a codon without changing theprimary amino acid sequence. Consequently, although the sequencesdescribed in this application are known to encode the Sps proteinsdescribed herein, the degeneracy of the code may be exploited to yieldvariant nucleic acid sequences which encode the same primary amino acidsequences.

The present invention may further provide modified Sps proteins. Forexample, a “modified” Sps protein may be chemically and/or enzymaticallyderivatised at one or more constituent amino acids, including side chainmodifications, backbone modifications, and N- and C-terminalmodifications including acetylation, hydroxylation, methylation,amidation, phosphorylation and the attachment of carbohydrate or lipidmoieties, cofactors, and the like.

One of skill in this field will appreciate that the amino acid and/ornucleic acid sequences described herein may be used to generaterecombinant Sps genes/proteins and as such, the present inventionfurther contemplates methods of generating and/or expressing recombinantSps genes and/or proteins, and products for use in such methods.Accordingly, in addition to providing substantially purified or isolatedrecombinant Sps sequences, a second aspect of this invention providesDNA constructs comprising a replicable expression vector and nucleicacid encoding one or more of the Sps protein(s) described herein.

Expression vectors for the production of the molecules of the inventioninclude plasmids, phagemids, viruses, bacteriophages, integratable DNAfragments, and other vehicles, which enable the integration of DNAfragments into the genome of the host. Expression vectors are typicallyself-replicating DNA or RNA constructs containing the desired gene orits fragments, and operably linked genetic control elements that arerecognised in a suitable host cell to effect expression of the desiredgenes.

Generally, the genetic control elements can include a prokaryoticpromoter system or a eukaryotic promoter expression control system. Suchsystems typically include a transcriptional promoter, an optionaloperator to control the onset of transcription, transcription enhancersto elevate the level of RNA expression, a sequence that encodes asuitable ribosome binding site, RNA splice junctions, sequences thatterminate transcription and translation and so forth. Expression vectorsusually contain an origin of replication that allows the vector toreplicate independently of the host cell.

A vector may additionally include appropriate restriction sites,antibiotic resistance or other markers for selection of vectorcontaining cells.

Plasmids are the most commonly used form of vector but other forms ofvectors which serve an equivalent function and which are, or become,known in the art are suitable for use herein. See, e.g., Pouwels et al.Cloning Vectors: a Laboratory Manual (1985 and supplements), Elsevier,N.Y.; and Rodriquez, et al. (ads.) Vectors: a Survey of MolecularCloning Vectors and their Uses, Buttersworth, Boston, Mass. (1988).

In general, such vectors may contain specific genes, which are capableof providing phenotypic selection in transformed cells. The use ofprokaryotic and eukaryotic viral expression vectors to express thenucleic acid sequences coding for the recombinant proteins of thepresent invention are also contemplated.

The vector is introduced into a host cell by methods known to those ofskill in the art. Introduction of the vector into the host cell can beaccomplished by any method that introduces the construct into the cell,including, for example, electroporation, heat shock, chemical compoundssuch, for example, calcium phosphate, stronitium phosphate,microinjection techniques and/or gene guns. See, e.g., Current Protocolsin Molecular Biology, Ausuble, F. M., ea., John Wiley & Sons, N.Y.(1989).

Another aspect relates to a host cell transformed with any one of thenucleic acid constructs of the present invention. Suitable host cellsinclude prokaryote cells, lower eukaryotic and higher eukaryotic cells.Prokaryotes include Gram negative and Gram positive organisms, e.g., E.coli and B. subtilis. Lower eukaryotes include yeast, S. cerevisiae andPichia, and species of the genus Diclyostelium.

“Host cell” as used herein refers to cell which can be recombinantlytransformed with vectors constructed using recombinant DNA techniques.

A drug resistance or other selectable marker is intended in part tofacilitate the selection of the transformants. Additionally, thepresence of a selectable marker, such as a drug resistance marker may beof use in keeping contaminating microorganisms from multiplying in theculture medium. Such a pure culture of the transformed host cells wouldbe obtained by culturing the cells under conditions which require theinduced phenotype for survival.

PCR techniques may be exploited to selectively obtain Sps gene sequencesfrom samples of Staphylococcal DNA. These amplified sequences may beintroduced into any of the vectors described above. In one embodiment,the vector may further comprise a nucleotide sequence of a tag or labelto assist in protein purification procedures.

Techniques used to purify recombinant proteins generated in this way areknown and, where the recombinant protein is tagged or labelled, thesemay include the use of, for example, affinity chromatography techniques.

In view of the above, a fourth aspect of this invention provides aprocess for the production of recombinant Sps protein(s) or peptide(s)of the invention, said process comprising the steps of (a) transforminga host cell with the nucleotide sequence of the invention ortransfecting a host cell with a nucleic acid construct of the invention;(b) culturing the cells obtained in (a) under conditions in whichexpression of the protein takes place; and (c) isolating the expressedrecombinant protein or peptide from the cell culture or/and the culturesupernatant.

The polypeptide may be partially purified from the host and where thepolypeptide is secreted from the host cell, the cells may be separatedfrom the media by centrifugation, the cells being pelleted.Alternatively, the polypeptide may be partially purified from thissupernatant, for example using affinity chromatography.

A fifth aspect of this invention provides monoclonal or polyclonalantibodies, whether derived from rodents, mammals, avians, ungulates, orother organisms, that bind to the Sps proteins described herein.Production and isolation of monoclonal and polyclonal antibodies to aselected polypeptide sequence is routine in the art see for example“Basic methods in Antibody production and characterisation” Howard &Bethell, 2000, Taylor & Francis Ltd. Such antibodies may be used indiagnostic procedures, as well as for passive immunisation.

Staphylococcus pseudintermedius is known to cause cutaneous inflammatorydiseases in a variety of animals. One such cutaneous inflammatorydisease is canine pyoderma which is a major cause or morbidity in dogs.Pydoderma associated with Staphylococcus pseudintermedius infection iscommon among dogs and is often associated with puritis, alopecia,erythema and swelling. At present, the treatment of this infection isdifficult, requiring the use of aggressive, systemically administeredantibiotics. The present inventors have discovered that Sps genes (andtheir protein products) play a role in Staphylococcus pseudintermediuscolonisation and pathogenesis. As such, the Sps genes and proteinsdescribed herein may find application in the treatment and/or preventionof cutaneous disorders such as canine pyoderma.

Accordingly, a sixth aspect of this invention provides an Sps protein orgene as substantially defined above, for use in raising an immuneresponse in an organism. The proteins and genes described herein mayfind particular application as a vaccine, but could also be used toobtain an immune serum potentially useful in passive vaccinationtechniques.

Advantageously, the invention may provide a vaccine for use inpreventing or controlling disease in canine species caused orcontributed to by Staphylococcus pseudintermedius. In other embodiments,the vaccines provided by this invention may be used to protect againstthe development of infections caused or contributed to by Staphylococcuspseudintermedius. In other embodiments, the vaccines may be used toprotect against instances of canine pyoderma.

In one embodiment, the vaccine may be a polypeptide and/orpolynucleotide vaccine.

A polynucleotide vaccine may comprise a polynucleotide fragment,preferably a DNA fragment, having a nucleotide sequence encoding anantigenic polypeptide comprising at least an antigenic portion any oneor more of the Sps proteins described herein. Vaccines of this type mayotherwise be referred to as “DNA vaccines”—such vaccines may beintroduced to host cells (such as mammalian, for example, canine cells)where they express antigens which elicit immune responses.

A polypeptide or protein vaccine may comprises one or more of the Spsproteins (or antigentic fragments or portions) described herein. One ofskill will appreciate that the one or more Sps protein(s) may benaturally occurring and isolated from Staphylococcus pseudintermedius,or recombinant.

A protein vaccine may be administered by any suitable route.Advantageously, a protein vaccine may be administered orally (byingestion), topically or by direct injection—preferably intraperitonealor intramuscular injection. A protein subunit vaccine formulated fororal administration can contain the polypeptide encapsulated in forexample, a biodegradable polymer as described hereinafter.

In view of the above, the invention further provides a method ofimmunising a dog against Staphylococcus pseudintermedius, said methodcomprising administering to the dog a DNA or protein vaccine of theinvention.

Conveniently, the protein vaccines described herein may further includeor comprise one or more adjuvant(s). Further, one or more boostervaccinations are preferably administered at time periods subsequent tothe initial administration to create a higher level of immune responsein the animal.

In yet another aspect, the vaccine of the invention may comprise afusion protein comprising a carrier polypeptide and one or more Spsprotein(s) of the invention. The Sps protein(s) for use in this aspectof the invention can itself be antigenic or non-antigenic; inembodiments wherein the protein is non-antigenic, the carrierpolypeptide is antigenic, stimulating the immune system to react to thefusion protein thereby generating an immune response in an organism—suchas, for example a canine immune response to Staphylococcuspseudintermedius. A non-antigenic protein thus functions as a hapten. Anexample of an antigenic carrier polypeptide is keyhole limpet hemocyanim(KLH). Conventional fusion constructs between carriers such asglutathione sulfotransferase (GST) and said Sps protein(s) of theinvention are also included as protein vaccines according to theinvention, as are fusions of the Sps protein(s) and an affinity tag suchas a polyhistidine sequence. A fusion construct may be preferred for useas a protein vaccine when the antigenic Sps analog, fragment, ormodification thereof is small.

In a seventh aspect, the present invention provides a method forimmunising dogs against Staphylococcus pseudintermedius, said methodcomprising administering to the dog a vaccine of the invention.

A polynucleotide vaccine may further comprises a promoter, such as theCMV promoter, operably linked to the coding sequence for the Spspolypeptide or antigenic fragment thereof (e.g., U.S. Pat. No. 5,780,44,Davis). The polynucleotide may be cloned within a vector such as aplasmid. There are numerous plasmids known to those of ordinary skill inthe art useful for the production of polynucleotide vaccines.

Other possible additions to the polynucleotide vaccine constructsinclude nucleotide sequences encoding cytokines, such as granulocytemacrophage colony stimulating factor (GM-CSF), interleukin-12 (IL-12)and co-stimulatory molecules such B7-1, B7-2, CD40. The cytokines can beused in various combinations to fine-tune the response of the animal'simmune system, including both antibody and cytotoxic T lymphocyteresponses, to bring out the specific level of response needed to affectthe animal's reproductive system. A polynucleotide vaccine of theinvention can also encode a fusion product containing the antigenicpolypeptide and a molecule, such as CTLA-4, that directs the fusionproduct to antigen-presenting cells inside the host.

Plasmid DNA can also be delivered using attenuated bacteria as deliverysystem, a method that is suitable for DNA vaccines that are administeredorally. Bacteria are transformed with an independently replicatingplasmid, which becomes released into the host cell cytoplasm followingthe death of the attenuated bacterium in the host cell. An alternativeapproach to delivering the polynucleotide to an animal involves the useof a viral or bacterial vector. Examples of suitable viral vectorsinclude adenovirus, polio virus, pox viruses such as vaccinia, canarypox, and fowl pox, herpes viruses, including catfish herpes virus,adenovirus-associated vector, retroviruses and bacteriophage. Exemplarybacterial vectors include attenuated forms of Salmonella, Shigella,Edwardsiella ictaluri, and Yersinia ruckeri. Preferably, thepolynucleotide is a vector, such as a plasmid, that is capable ofautologous expression of the nucleotide sequence encoding said Spsprotein or fragment thereof.

In one embodiment, the vaccine may be a DNA vaccine comprising a DNAfragment having a nucleotide sequence that encodes a polypeptide havingan amino acid sequence homologous or identic to a sequence selected fromthe group consisting of SEQ ID NOS: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20,22, 24, 26, 28, 30, 32, 34, 36 or 37 or an antigenic analog, fragment,or modified version thereof.

Polynucleotide-based immunisation induces an immune response to anantigen expressed in vivo from a heterologous polynucleotide fragmentintroduced into a cell. DNA vaccine may be particularly useful as theheterologous nucleic acid expression may continue for a length of timesufficient to induce a relatively strong and sustained immune responsewithout the need for subsequent “booster” vaccinations, as may berequired when using protein based vaccines. A polynucleotide vaccinecomprising a polynucleotide fragment having a nucleotide sequenceencoding said Sps can be administered to dog (or rather to a particulartissue or cells thereof) using biolistic bombardment, ingestion ordirect injection, as described for example, in U.S. Pat. No. 5,780,448(Davis), preferably intraperitoneal or intramuscular injection. Apreferred method of administration is biolistic bombardment, as with a“gene gun”. A polynucleotide vaccine formulated for oral administrationpreferably contains DNA encapsulated in a biodegradable polymer.Examples of a suitable biodegradable polymer include chitosan and homo-or co-polyers of polylactic acid and polyglycolic acid. Accordingly, thepresent invention further provides a method for immunising dogs againstStaphylococcus pseudintermedius by administering to the dog apolynucleotide vaccine of the invention, preferably a DNA vaccine.

Other methods of administering nucleic acid vaccines of the typedescribed herein may include, for example, use of the technologydescribed in WO02/076498.

The amount of protein/polynucleotide vaccine to be administered to ananimal depends on the type and size of animal, the condition beingtreated, and the nature of the protein/polynucleotide, and can bereadily determined by one of skill in the art. In some applications, oneor more booster administrations of the protein/polynucleotide vaccine attime periods subsequent to the initial administration are useful tocreate a higher level of immune response in the animal.

In one embodiment of the vaccine of the invention and/or Sps proteinsdescribed herein (including antigenic fragments, analogs or modifiedversion thereof) may be linked, for example, at its carboxy-terminus, toa further component. The further component may serve to facilitateuptake of the Sps protein, or enhance its immunogenicity/processing.

The immune-stimulating compositions of the invention may be optionallymixed with excipients or diluents that are pharmaceutically acceptableas carriers and compatible with the active component(s). The term“pharmaceutically acceptable carrier” refers to a carrier(s) that is“acceptable” in the sense of being compatible with the other ingredientsof a composition and not deleterious to the recipient thereof. Suitableexcipients are well known to the person skilled in the art. Examplesinclude; water, saline (e.g. 0.85% sodium chloride; see Ph.Eur.monograph 2001:0062), buffered saline, fish oil with an emulsifier (e.g.a lecithin, Bolec MT), inactivant (e.g. formaldehyde; see Ph.Eur.monograph 1997:0193), mineral oils, such as light mineral oils,alhydrogel, aluminium hydroxide. Where used herein, the term “oiladjuvant” to embraces both mineral oils and synthetic oils. A preferredadjuvant is Montanide ISA 711 (SeppicQuai D'Orsay, 75321 Paris, France)which is a manide oleate in an oil suspension. In addition, if desired,the immune-stimulating composition (including vaccine) may contain minoramounts of auxiliary substances such as wetting or emulsifying agents,pH buffering agents, and/or adjuvants which enhance the effectiveness ofthe immune-stimulating composition.

A vaccine composition may be administered as a course of a number ofdiscrete doses over a period of time. For example it may be administeredover a period of around 2-21 days.

Vaccination may be repeated at daily, twice-weekly, weekly or monthlyintervals. For example a boost vaccination may be administered after theinitial dose. For example a boost may be administered at around 4-14weeks after the vaccination. The initial vaccination and any boost maybe carried out using the same or different modes of administration. Forexample, the initial may be by injection and the boost may be by oraladministration. An example regime includes a first vaccination byinjection, followed by a course of orally administered boost vaccine, ora booster prior to an expected outbreak. However, it will be appreciatedthat any suitable route of administration(s) and/or regime(s) may beemployed.

Additionally, knowledge of the Sps protein nucleotide and amino acidsequences set forth herein opens up new possibilities for detecting,diagnosing and characterising Staphylococcus pseudintermedius in caninepopulations. For example, an oligonucleotide probe or primer based on aconserved region of one or more of the Sps proteins described herein,may be used to detect the presence of the Sps protein in or on a caninehost.

Vaccines may contain one or more of the Sps proteins/nucleic acids/genesdescribed herein (i.e. those shown as SEQ ID NOS: 1-38). In oneembodiment, the vaccine may comprise a cocktail of Sps proteins/peptidesand or nucleic acids. Typically, a cocktail may comprise 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37 or 38 Sps nucleic acidand/or protein/peptide components (for example (2 or more) componentshaving sequences homologous or identical to any of SEQ ID NOS: 1-38).

Furthermore, the vaccines may contain bacterial antigens used to controlother diseases, for example diseases caused by other Staphylococcalspecies and/or antigens to treat, prevent or control diseases and/orconditions with other aetiologies or caused or contributed to by otherpathogens. As such, the vaccine compositions described herein may findapplication in multivalent vaccines including antigens against othercanine diseases.

In addition to vaccines and/or immunogenic compositions comprising oneor more of the Sps proteins described herein, the present inventionfurther provides compounds for treating infections caused or contributedto by Staphylococcus pseudintermedius or compounds for the preparationof medicaments for treating the same.

In one embodiment, the compound may be a small organic molecule,antibody, peptide or carbohydrate which antagonises the interactionbetween the Sps protein and its ligand (an extracellular matrix (ECM)protein). For example, the compound may be a synthetic peptidecomprising or based on, the sequence of an ECM protein known to interactwith a particular Sps protein, or the sequence of a protein given abovewhich may interfere with binding between the wild type S.psedintermedius protein and its ligand. Additionally or alternatively,binding agents, such as for example, antibodies with specificity oraffinity for one or more Sps protein ligands, may also be used toantagonise the Sps/ligand interaction. Therapeutic approaches of thistype may prevent Staphylococcus pseudintermedius colonising orbinding/adhering to cells.

In view of the above, the invention may relate to methods of treatinginfections caused or contributed to by Staphylococcus pseudintermedius,said method comprising administering to an animal a therapeuticallyeffective amount of a compound which antagonises Sps/ligandinteractions.

In a further aspect, the present invention provides pharmaceuticalcompositions comprising a compound which antagonises Sps/ligandinteractions together with a pharmaceutical excipient, carrier ordiluent.

One of skill will appreciate that the vaccines, methods, uses ormedicaments comprising any of the Sps genes/nucleic acids and/orproteins and/or antagonistic compounds (for example Sps protein/nucleicacid fragments and/or antibodies) described herein may be combined withone or more other compounds for treating one or more other conditions—inparticular one or more other skin conditions. Said other skin conditionmay be, for example, atopic dermatitis.

In a further aspect, the present invention provides methods ofdiagnosing infections, diseases and/or conditions caused or contributedto by S. pseudintermedius, said methods comprising the steps ofidentifying in a sample provided by a subject suspected of sufferingfrom an infection, disease and/or conditions S. pseudintermedius causedor contributed to by S. pseudintermedius, a level of a protein, peptideor nucleic acid (for example a gene) encoded by a sequence provided bySEQ ID NOS: 1-38 or a fragment, portion, mutant, derivative and/orhomologoue/orthologue thereof.

It should be understood that all methods of diagnosis or detectiondescribed herein, may include an optional step in which the results arecompared with the results of a control sample, which does not comprisesequences derived from S. pseudintermedius, in particular sequencescorresponding to those provided as SEQ ID NOS: 1-38 disclosed herein.

The term “sample” may be taken to mean any sample comprising proteinand/or nucleic acid. For example, a “sample” may comprise a bodilyfluids such as whole blood, plasma, serum, saliva, sweat and/or semen.In other instances “samples” such as tissue biopsies and/or scrapingsmay be used. In particular, cutaneous (i.e. skin) tissue biopsies and/orscrapings may be used. Advantageously such biopsies may comprise cellsobtained from lesions suspected of resulting from or being associatedwith a S. pseudintermedius. Specifically, a biopsy, tissue sample orscraping may comprise cells derived from lesions exhibiting pathologycharacteristic of the S. pseudintermedius disease, pyoderma(particularly caninine pyoderma).

In addition, a sample may comprise a tissue or gland secretion andwashing protocols may be used to obtain samples of fluid secreted intoor onto various tissues, including, for example, the skin. One of skillin this field will appreciate that the samples described above may yieldor comprise quantities of nucleic acid (i.e. DNA or RNA) encoding all orpart of the various proteins described herein as well as quantities ofproteins or peptides (or fragments thereof) encoded thereby. In oneembodiment, the sample may comprise quantities of nucleic acid/peptidehaving or comprising the sequences given as SEQ ID NOS: 1-38.

One of skill in the art will be familiar with the techniques that may beused to identify levels of certain nucleic acid sequences and/orproteins, such as, for example, levels of the sequences given as SEQ IDNOS: 1-38 described herein (or a fragment, portion, mutant, derivativeand/or homologoue/orthologue thereof).

For example, PCR based techniques may be used to detect levels of geneexpression or gene quantity in a sample. Useful techniques may include,for example, polymerase chain reaction (PCR) or reverse transcriptase(RT)-PCR based techniques in combination with real-time PCR (otherwiseknown as quantitative PCR).

Additionally, or alternatively, a level of gene/protein expression maybe identified by way of microarray analysis. Such a method would involvethe use of a DNA micro-array which comprises nucleic acid derived fromone or more of the nucleic acid sequences described herein (for exampleSEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31,33, 35, 38). To identify a level of gene expression, one of skill in theart may extract nucleic acid, preferably mRNA, from a sample and subjectit to an amplification protocol such as, for example RT-PCR to generatecDNA. Preferably, primers specific for a certain mRNA sequence—in thiscase a S. pseudintermedius sequence comprised with any of, for example,SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31,33, 35, 38.

The amplified cDNA may be subjected to a further amplification step,optionally in the presence of labelled nucleotides (as described above).Thereafter, the optionally labelled amplified cDNA may be contacted withthe microarray under conditions which permit binding with the DNA of themicroarray. In this way, it may be possible to identify a level of S.pseudintermedius gene expression.

Further information regarding the PCR based techniques described hereinmay be found in, for example, PCR Primer: A Laboratory Manual, SecondEdition Edited by Carl W. Dieffenbach & Gabriela S. Dveksler: ColdSpring Harbour Laboratory Press and Molecular Cloning: A LaboratoryManual by Joseph Sambrook & David Russell: Cold Spring HarbourLaboratory Press.

In addition, other techniques such as deep sequencing and/orpyrosequencing may be used to detect cSCC sequences in any of thesamples described above. Further information on these techniques may befound in “Applications of next-generation sequencing technologies infunctional genomics”, Olena Morozovaa and Marco A. Marra, GenomicsVolume 92, Issue 5, November 2008, Pages 255-264 and “Pyrosequencingsheds light on DNA sequencing”, Ronaghi, Genome Research, Vol. 11, 2001,pages 3-11.

In addition to the molecular detection methods described above, one ofskill will also appreciate that immunological detection techniques suchas, for example, enzyme-linked immunosorbent assays (ELISAs) may be usedto identify levels of S. pseudintermedius proteins in samples. In otherembodiments, ELISPOT, dot blot and/or Western blot techniques may alsobe used. In this way, samples provided by subjects suffering from S.pseudintermedius related diseases and/or infections (for example caninesubjects suffereing from canine pyoderma), may be probed for levels ofone or more S. pseudintermedius proteins, particularly those encoded bySEQ ID NOS: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32,34, 36, or 37 so as to detect the presence of such proteins in a samplewhich may indicate a S. pseudintermedius infection.

Immunological detection techniques, may require the use of a substrateto which an antibody and/or antigen may be bound, conjugated orotherwise immobilised.

Suitable substrates may comprise, for example, glass, nitrocellulose,paper, agarose and/or plastic. A substrate which comprises, for example,a plastic material, may take the form of a microtitre plate.

Further information regarding ELISA procedures and protocols relating tothe other immunological techniques described herein may be found inUsing Antibodies: A Laboratory Manual by Harlow & Lane (CSHLP: 1999) andAntibodies: A Laboratory Manual by Harlow & Lane (CSHLP: 1988).

The present invention also extends to kits comprising reagents andcompositions suitable for diagnosing, detecting or evaluating possibleS. pseudintermedius infections, diseases and/or conditions. Kitsaccording to this invention may be used to identify and/or detect levelsof S. pseudintermedius gene(s)/S. pseudintermedius protein(s) insamples. Depending on whether or not the kits are intended to be used toidentify levels of S. pseudintermedius genes and/or S. pseudintermediusproteins in samples, the kits may comprise substrates having S.pseudintermedius proteins or agents capable of binding S.pseudintermedius proteins, bound thereto. In addition, the kits maycomprise agents capable of binding S. pseudintermediusproteins—particularly where the kit is to be used to identify levels ofone or more S. pseudintermedius proteins in samples. In otherembodiments, the kit may comprise polyclonal antibodies or monoclonalantibodies which exhibit specificity and/or selectivity for one or moreS. pseudintermedius proteins. Antibodies for inclusion in the kitsprovided by this invention may be conjugated to detectable moieties.Kits for use in detecting the expression of genes encoding S.pseudintermedius proteins may comprise one or moreoligonucleotides/primers for detecting/amplifying/probing samples for S.pseudintermedius protein encoding sequences. The kits may also compriseother reagents to facilitate, for example, sequencing, PCR and/or RFLPanalysis. In one embodiment, the kits may comprise one or moreoligonucleotides/primers for detecting/amplifying/probing nucleic acidsamples (for example nucleic acid derived from canine skin) for levelsof sequences corresponding to all or part of those described as SEQ IDNOS: 1-38 herein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1: Genomic location of the 17 genes encoding putative CWA proteinsin S. pseudintermedius strain ED99.

FIG. 2: Distribution of the genes encoding putative CWA proteins among20 S. pseudintermedius strains, representatives of the closely relatedS. delphini and S. intermedius, and other staphylococcal speciesassociated with animal skin disease.

FIG. 3: SDS-PAGE analysis (A) and Western blot analysis (B) of cellwall-associated proteins of S. Pseudintermedius ED99 and L. lactisexpressing SpsD, SpsL, and SpsO with sera from dogs diagnosed withpyoderma.

FIG. 4. Adherence of L. lactis expressing specified MSCRAMMs to humanFn.

FIG. 5. Adherence of L. lactis expressing specified MSCRAMMs to Fg fromdifferent animal sources.

FIG. 6. Adherence of L. lactis expressing specified MSCRAMMs to CK10.

FIG. 7. Adherence of L. lactis expressing different MSCRAMMs to caninecorneocytes of five dogs.

FIG. 8: SDS-PAGE analysis (A) and Western blot analysis (B) of Sps D,Sps L and Sps O recombinant A domain with canine convalescent serum frompyoderma cases.

FIG. 9: Inhibition of adherence of L. lactis expressing SpsD (A) andSpsL (B), and S. aureus Newman (C) to fibrinogen by canine convalescentserum from pyoderma cases.

DETAILED DESCRIPTION

The invention will now be described in more detail with reference to thefollowing Figures which show:

FIG. 1. Genomic location of the 17 genes encoding putative CWA proteinsin S. pseudintermedius strain ED99. Eight genes are situated in the oriCenviron, indicated in orange, and nine are located in the core genome.sps=S. pseudintermedius surface protein.

FIG. 2. Distribution of the genes encoding putative CWA proteins among20 S. pseudintermedius strains, representatives of the closely relatedS. delphini and S. intermedius, and other staphylococcal speciesassociated with animal skin disease. The diversity of strains isrepresented a phylogenetic tree; grey squares indicate that the gene ispresent, blank squares that the gene is absent based on Southern blotanalysis (for spsA to spsO), or PCR amplification (for spsP and spsQ).

FIG. 3. Western blot analysis of cell wall-associated proteins of S.pseudintermedius ED99 and L. lactis expressing SpsD, SpsL, and SpsO withsera from dogs diagnosed with pyoderma. (A) SDS PAGE analysis and (B)Western blot analysis of protein fractions from S. pseudintermedius ED99in exponential phase of growth (lane 1); L. lactis expressing SpsL (lane2); L. lactis expressing SpsD (lane 3); L. lactis expressing SpsO (lane4); and L. lactis with pOri23 alone (lane 5).

FIG. 4. Adherence of L. lactis expressing specified MSCRAMMs to humanFn. Plates were coated with 1 μg of human Fn or 1 μg of BSA per well.Absorbance was measured at 590 nm and results are expressed as meanvalues of triplicate samples. Error bars indicate standard deviation. L.lactis expressing FnbpA from S. aureus and PBS were included ascontrols.

FIG. 5. Adherence of L. lactis expressing specified MSCRAMMs to Fg fromdifferent animal sources. Plates were coated with 1 μg of Fg or 1 μg ofBSA per well. Absorbance was measured at 590 nm and results areexpressed as mean values of triplicate samples. Error bars indicatestandard deviation. L. lactis expressing FnbpA from S. aureus and PBSwere included as controls.

FIG. 6. Adherence of L. lactis expressing specified MSCRAMMs to CK10.Plates were coated with 1 μg of recombinant CK10 or 1 μg of BSA perwell. Absorbance was measured at 590 nm and results are expressed asmean values of triplicate samples. Error bars indicate standarddeviation. S. aureus strain SH1000 in exponential and stationary phasesof growth and PBS were included as controls.

FIG. 7. Adherence of L. lactis expressing different MSCRAMMs to caninecorneocytes of five dogs. Bacterial adherence is calculated aspercentage area covered with bacterial cells per field of corneocytes(ROI=500 μm²). Results are based on the arithmetic mean of duplicateexperiments. The bottom of each box represents the first quartile (Q1),the top of the box the third quartile (Q3), the bold lines the median,and the black circles the mean values. The whiskers define the range ofthe data.

FIG. 8: Reactivity of canine convalescent serum from pyoderma cases toSps D, Sps L and Sps O recombinant A domain. 1 ug aliquots of rSps D andrSps L, and 10 μl volumes of purified rSps O were subjected to SDS-PAGEunder standard conditions and Coomassie stained (A) or Western blottransferred onto a nitrocellulose membrane. Membranes were probed with a1:1000 dilution of canine serum, followed by a 1:3000 dilution ofHRP-conjugated sheep anti-canine IgG. Reactive bands were visualized onChemi-luminescent Film (B). 5 μl aliquots of recombinant ClfB and thesuperantigen SEI from S. aureus were included in the terminal lanes ofeach gel as negative controls.

FIG. 9: Inhibition of adherence of L. lactis expressing SpsD (A) andSpsL (B) to fibrinogen (2 μg per well) by canine convalescent serum frompyoderma cases. Bacterial cultures, normalised to an OD600 of 1 in PBSwere pre-incubated for 2 h with doubling dilutions of serum ranging from2% to ˜0.01% (v/v), prior to inoculation into fibrinogen coated wells.Results (n=3, ±SD) are expressed as absorbance readings at 590 nm minusbackground levels of fluorescence. Background fluorescence was measuredby inoculating control cultures, incubated for 2 h in the absence ofserum, into wells coated with BSA (2 μg per well). Incubations of S.aureus Newman (C) were included as a negative control.

EXAMPLES Example 1 Materials and Methods Genome-Wide Screen for GenesEncoding for Cell-Wall Anchored Proteins

The S. pseudintermedius strain ED99 draft genome was interrogated forhomologous sequences using position specific iterative basic localalignment search tool (PSI-BLAST), available from the National Centerfor Biotechnology Information (NCBI), USA(http://blast.ncbi.nlm.nih.gov/Blast.cgi), and for the presence of aLPX[TSA][GANS] motif pattern by pattern hit initiated basic localalignment search tool (PHI-BLAST), available from NCBI(http://blast.ncbi.nlm.nih.gov/Blast.cgi). Signal sequences werepredicted by employing the SignalP server(http://www.cbs.dtu.dk/services/SignalP/), provided by the Center forBiological Sequence Analysis (CBS), Technical University of Denmark.

In Silico Structural Analysis of Cell-Wall Anchored Proteins

The predicted CWA proteins were searched for functional domains usingEMBL-EBI InterPro Scan (http://www.ebi.ac.uk/interpro). Structuralanalysis was carried out with the PHYRE (Protein Homology/analogYRecognition Engine) fold recognition server, available from theStructural Bioinformatics Group, Imperial College London, UK(http://www.sbg.bio.ic.ac.uk/phyre/). Repeat sequences were predicted bygenerating nucleic acid dot plots, using software available fromColorado State University, USA(http://www.vivo.colostate.edu/molkit/dnadot/), applying tandem repeatsfinder software from Boston University, USA(http://tandem.bu.edu/trf/trf.html), and variable sequence tandemrepeats extraction and architecture modelling (XSTREAM), available fromthe University of California, USA(http://jimcooperlab.mcdb.ucsb.edu/xstream/). Sequence alignments andpair-wise sequence comparisons were generated with ClustalW2(http://www.ebi.ac.uk/Tools/clustalw2). Amino acid composition andmolecular weight predictions were generated using ProtParam on theExPASy Proteomics Server (http://www.expasy.ch/tools/protparam.html).

Cloning of Selected Genes Encoding Putative MSCRAMMs of S.pseudintermedius ED99 into L. lactis MG1363

Oligonucleotides were designed for PCR amplification of the full-lengthspsD, spsL and spsO genes and either PstI, SalI or BamHI specificrestriction sites were inserted on both sides of the DNA fragments. 50μl PCR reactions contained 2 μl (approximately 100 ng) genomic DNAtemplate, 0.25 μM forward primer, 0.25 μM reverse primer, 1×PfuUltra™ IIreaction buffer (Stratagene, USA), 0.25 mM dNTP's (Promega, USA) and 1μl PfuUltra™ II Fusion HS DNA polymerase (Stratagene, USA). Thethermocycler programme included an initial denaturation step at 95° C.for 2 min, followed by 30 cycles of denaturation at 95° C. for 20 s,annealing at 50° C. for 20 s and extension at 72° C. for 2 min, followedby a final extension step at 72° C. for 3 min. PCR products werevisualised on 0.8% (w/v) agarose gels, gel extracted under avoidance ofUV light exposure and purified using QIAquick Gel Extraction Kit(Qiagen, UK) according to the manufacturer's instructions. Purified DNAfragments were cloned into the StrataClone™ Blunt PCR cloning vectorpSC-B (Stratagene, USA) using the StrataClone Ultra™ Blunt PCR CloningKit (Stratagene, USA) according to the manufacturer's instructions. Eachcloning reaction consisted of 3 μl Strataclone Buffer Blunt (Stratagene,USA), 2 μl purified PCR product and 1 μl Strataclone™ Blunt Vector Mix(Stratagene, USA). StrataClone™ SoloPack® competent cells (Stratagene,USA) were transformed according to the manufacturer's instructions andcolonies selected using blue-white screening on LB-ampicillin (100μg/ml)-X-gal plates. White colonies were transferred into 5 mlLB-ampicillin (100 m/ml) broth and grown overnight at 37° C. withshaking at 200 rpm. Plasmid was isolated using QIAprep Spin Miniprep Kit(Qiagen, UK) according to the manufacturer's instructions. Purifiedplasmids were digested using appropriate restriction endonucleases (NewEngland Biolabs, UK), and diagnostic digests were analysed on 0.8% (w/v)agarose gels. For generating DNA constructs, the E. coli-L. lactisshuttle vector pOri23 (kindly provided by P. Moreillon, University ofLausanne, Switzerland) was used. The pOri23 vector carries the ermAMgene for erythromycin resistance, the high-copy-number oriColE1 repliconfor autonomous replication in E. coli and the constitutive lactococcalpromoter P23 (Que et al., 2000). The multiple cloning site of pOri23consists of restriction sites for endonucleases PstI, SalI and BamHI(Que et al., 2000).

StrataClone™ plasmids containing the DNA inserts of interest and the E.coli-L. lactis shuttle vector pOri23 were each digested in a 100 μltotal reaction volume containing 10 μl plasmid (approximately 2.5 μg),20 units appropriate restriction endonucleases (New England Biolabs,UK), and suitable buffers (New England Biolabs, UK) according to themanufacturer's instructions. Restriction digestions were performed at37° C. for 16 h. The restriction fragments to be cloned were extractedfrom 0.8% (w/v) agarose gels without UV exposure as described in thegeneral Material and Methods and purified using QIAquick Gel ExtractionKit (Qiagen, UK) according to the manufacturer's instructions. DNAinserts and restriction-digested pOri23 plasmid were quantified usingspectrophotometry (NanoDrop ND-1000, Thermo Scientific, USA) andligation reactions were carried out with a plasmid to insert ratio of1:3 in a 10 μl total ligation reaction volume, consisting of 1 μl vector(approximately 10 ng), 400 units T4 DNA ligase (New England Biolabs,UK), lx T4 DNA ligase reaction buffer (New England Biolabs, UK), x illDNA insert (depending on DNA concentration), and x μl sterile water(depending on the volume of DNA insert). Ligations were incubated at 16°C. for 16 h.

One 50 μl aliquot of electrocompetent L. lactis cells was thawed on iceand 2 μl (˜20 ng) pOri23 plasmid carrying the DNA insert of interest wasadded. Electroporation cuvettes (Sigma-Aldrich, UK) were pre-chilled andL. lactis cells plus plasmid were transferred into the cuvettes.Electroporation was performed at standard settings (25 μF, 2.5 kV, 200Ohm) and 1 ml GM17 was added immediately. Cells were incubated at 30° C.in a static incubator for 2 h prior to spreading 250 μl of cellsuspension per plate onto GM17 plates containing 5 μg/ml erythromycin.Plates were incubated overnight at 30° C.

For screening of L. lactis transformants, plasmid was isolated using theQiagen MiniPrep Kit (Qiagen, UK) with addition of 100 U/ml mutanolysin(Sigma-Aldrich, UK) and 100 m/ml lysozyme (Sigma-Aldrich, UK) to bufferP1. Diagnostic digests of purified plasmids were carried out withappropriate restriction enzymes and analysed on 0.8% (w/v) agarose gels.

Additionally, colony PCR was performed for pOri23 carrying spsD and spsOusing gene-specific oligonucleotides (Table 5.3). L. lactis colonieswere resuspended in 10 μl 10% (v/v) IGEPAL (Sigma-Aldrich, UK) andincubated for 10 min at 95° C. in a thermocycler machine. 40 μl mastermix containing 0.3 μM forward primer, 0.3 μM reverse primer, 0.2 mMdNTP's (Promega, USA), 1× reaction buffer (Promega, USA), 1.5 mM MgCl₂(Promega, USA) and 0.025 u/μl taq polymerase (Promega, USA) was added.The thermocycler programme included an initial denaturation step at 95°C. for 2 min, followed by 30 cycles of denaturation at 95° C. for 1 min,annealing at 50° C. for 1 min and extension at 72° C. for 1 min,followed by a final extension step at 72° C. for 7 min. PCR productswere visualised on 0.8% (w/v) agarose gels.

Western Blot Analysis of L. lactis Constructs

Samples were dissolved in 1× Laemmli sample buffer (Sigma-Aldrich, UK),boiled for 10 min and resolved by SDS-PAGE in 10% polyacrylamide gels bystandard procedures, and Western blot analysis was carried out asdescribed in the general Materials and Methods. Three canine serasamples from pyoderma cases (obtained from patients at the Hospital forSmall Animals, The Royal (Dick) School of Veterinary Studies, TheUniversity of Edinburgh) were pooled and used as primary antibody in a1:1000 dilution. HRP-conjugated sheep anti-dog antibody was used as asecondary antibody in a 1:5000 dilution (Bethyl Laboratories Inc., USA).

Canine Corneocyte Adherence Assay

For preliminary experiments to confirm adherence of S. pseudintermediusED99 and non-adherence of L. lactis, corneocytes were obtained from aseven-year-old male neutered Border collie cross-breed with no historyor physical signs of systemic or cutaneous disease. Corneocytes for theL. lactis adherence study were obtained from five dogs of differentbreeds (one Labrador retriever, two Border collies and twocross-breeds). Three dogs were ovariohysterectomised females and twowere entire males. The median age was seven years (range one to twelveyears). The dogs showed no abnormalities on general physical examinationand had no history or physical signs of skin disease at the time ofcorneocyte collection. All dogs were privately owned by staff orstudents of the Royal (Dick) School of Veterinary Studies, TheUniversity of Edinburgh. None of the dogs had received topical orsystemic drug treatments for at least three weeks prior to the day ofcorneocyte collection.

Samples were taken from the ventral abdomen and inner thigh. Ifnecessary, sample sites were clipped with Oster clippers (OsterCryotech, USA) using a number 40 blade. For collection of corneocytes,the method described by Forsythe et al. (2002) was used. Briefly, thearea was cleaned of surface debris and commensal bacteria by applyingfour strips of single sided adhesive tape (Cellux, Henkel ConsumerAdhesives, UK), using each strip once. To collect corneocytes,double-sided, clear, adhesive wig tape (Tropical Tape Super Grip, USA)was mounted onto a microscope slide in 1 cm² pieces and applied to thesame area of skin surface 10 times with gentle force. Slides wereinvestigated by microscopic examination and only slides with at least75% corneocyte coverage were used in the study.

The corneocyte slides were positioned in moisture chambers (Nunc™,Thermo Fisher Scientific, Denmark) as described by Forsythe et al.(2002). The moisture chambers consisted of 30 cm×30 cm plastic trayswith lids and were prepared by lining the trays with moistened papertowels. S. pseudintermedius ED99 stationary or exponential (OD₆₀₀ of0.5) phase cultures and L. lactis exponential phase cultures (OD₆₀₀ 0.6to 0.8) were centrifuged at 4000 rpm for 5 min, washed with PBS andresuspended in PBS to a final OD₆₀₀ of 0.5. The moisture chambers wereplaced in a static incubator and 250 μl of bacterial suspension wasadded to each 1 cm² of tape, forming a meniscus on the tape. Slidesincubated with 250 μl of sterile PBS were included as a control. Theslides were incubated at 37° C. for 90 min and washed in PBS. Each slidewas stained with 0.5% (w/v) crystal violet (Sigma-Aldrich, UK) for 90 sbefore rinsing off with PBS. The slides were air-dried and a drop ofimmersion oil (Cargille Laboratories Inc., USA) and a cover slip(Scientific Laboratory Supplies, UK) were added before microscopicquantification. All slides were prepared in duplicate on the same dayand incubated at the same time. Prior to incubation with bacterialsuspensions or PBS, each slide was labelled with a letter code to allowidentification after the microscopic analysis. The identification codeon each slide was hidden by a third party for subsequent imageacquisition so that the investigator was blinded to the origin of theslide. For quantification of adherent bacteria, computerised imageanalysis was used as described previously by Forsythe et al. (2002) withminor modifications. For each slide, bright field images of 1000×oil-immersion fields were acquired with a Sony DXC-390P 3CCD colourvideo camera (Scion Corporation, USA) connected to a Leica Laborlux Smicroscope (Leica Microsystems UK Ltd., UK). The RGB video signal fromthe camera was digitised using Scion Image (Scion Corporation, USA)installed in a G4 Macintosh computer (Apple Computer, USA) fitted with aCG-7 frame grabber (Scion Corporation, USA). For image acquisition,fields equivalent to 14.4 mm² were selected randomly by starting in thebottom left corner of each slide and moving through the slide in adefined way using the scale on the microscope stage. A field wasdiscarded if the corneocyte layer was not confluent, the bacteria werepoorly stained against the background or the field could not be focusedproperly. The software used for quantification of bacterial adherencewas set to calculate the percentage area that was covered by bacteriaper confluent layer of corneocytes in a defined region of interest (ROI)of 500 μm² within each image field acquired. Previous studies byForsythe et al. (2002) using the same technique and software havedemonstrated that 15 replicates of each duplicate slide resulted inacceptable coefficients of variation of approximately 10%. In thisstudy, 25 replicates of each slide were acquired and the overall meanpercentage area of adherence was determined by calculating the mean ofall replicates.

Results Identification of Genes Encoding 17 Putative Cell-Wall-AnchoredProteins in the S. Pseudintermedius ED99 Genome

The initial search for putative CWA proteins identified 34 sequencesthat fulfilled at least one of the search criteria (homology tocharacterised MSCRAMMs in the database, predicted LPXTG motif or variantnear the C terminus, predicted signal peptide at the N terminus). Aftergap closure and combination of incomplete sequences, a total of 17 ORFsencoding putative CWA proteins with a predicted minimum length ofapproximately 250 amino acids was determined. The 17 predicted CWAproteins were designated ‘Sps’ for Staphylococcus pseudintermediussurface proteins’, followed by a capital letter (SpsA to SpsQ). Theirposition in the S. pseudintermedius ED99 genome is indicated in FIG. 1.Of note, eight genes encoding putative CWA proteins are located near theoriC environ (FIG. 1). Homology searches in the database resulted insequence identities with known staphylococcal proteins ranging from ˜30%to ˜80% (Table 1). Signal sequences, necessary for Sec-dependent proteinsecretion (Foster and Hook, 1998), were predicted for 14 putative Spsproteins, consisting of 29 aa for SpsC and SpsK, 33 aa for SpsN, SpsP,and SpsQ, 36 aa for SpsD, 37 for SpsG, 38 aa for SpsA, SpsB, and SpsL,39 aa for SpsH, 44 aa for SpsO, and 48 aa for SpsF and SpsM. No signalsequence was predicted for SpsE, SpsI, and SpsJ (FIG. 4.3).

The Putative CWA Proteins SpsD, SpsL, and SpsO have Several MSCRAMMFeatures.

Out of the 17 putative CWA proteins of S. pseudintermedius ED99, SpsD,SpsL, and SpsO contained each of the MSCRAMM features screened for,including a signal sequence at the N-terminus, followed by anon-repeated A domain with two IgG-like folds, dividing the A domaininto N1, N2, and N3 subdomains, a tandemly repeated domain at theC-terminus (and at the N-terminus for SpsO), and a C-terminalLPXTG-anchor motif. The main characteristics of SpsD, SpsL, and SpsO aresummarised in Table 2. Of interest, a TYTFTDYVD motif or variant,important for the ‘dock, lock and latch’ ligand-binding mechanism(Ponnuraj et al., 2003), was found in SpsD, SpsL, and SpsO, and putativelatching sequences were identified (Table 2). Further, putativeFn-binding motifs with weak homology to FnbpA-10 of FnbpA in S. aureuswere detected in the repeat region of SpsL (24% identity in pair-wisealignments for SpsL1-SpsL6, and 21% for SpsL-7). No homology toFn-binding motifs of FnbpA was detected in the repeat regions of SpsDand SpsO. Of note, the genes encoding for SpsD, SpsL, and SpsO in the S.pseudintermedius ED99 genome are situated in different genomic contexts.While spsD is located in a well-conserved region of the core genome,spsL is part of the oriC environ (Takeuchi et al., 2005) (FIG. 1). ThespsO gene appears to be species-specific as it is not present in thegenomes of other staphylococcal species. The region contains twoputative transposases, suggesting that the whole region might besubjected to horizontal gene transfer.

Distribution of the 17 Genes Encoding Putative Cell-Wall-AnchoredProteins Among the S. intermedius Group

In order to investigate the distribution of the 17 genes encodingputative CWA proteins identified in the S. pseudintermedius ED99 genomeamong other members of the SIG and closely related staphylococcalspecies, Southern blot analysis and PCR amplification were performed. Atotal of 20 S. pseudintermedius strains representing the breadth ofdiversity within the species, representatives of the closely related S.delphini and S. intermedius species, and other staphylococcal speciesassociated with animal hosts (FIG. 2) were screened for the presence ofthe putative CWA encoding genes by Southern blot analysis (spsA tospsO). For the S. aureus spa orthologues spsP and spsQ, PCRamplification was employed, as the genes share 70% nucleotide identitywhich precluded design of gene-specific probes for Southern blotanalysis. For similar reasons, the primers designed for PCRamplification were located upstream of spsP (spsP-F), in thenon-repeated region of spsP (spsP-R), in the unique region between spsPand spsQ (spsQ-F), and in a region unique for spsQ (spsQ-R).

Of the 17 genes examined, 13 were found in all S. pseudintermediusstrains investigated. The remaining 4 (spsF, spsO, and the S. aureus spaorthologues spsP and spsQ) were present in 11, 6, 7, and 11 of the 20 S.pseudintermedius strains, respectively. Furthermore, 8 of the 17 geneswere detected in S. delphini and 6 in S. intermedius, and 9 genes wereexclusive to S. pseudintermedius. None of the genes encoding putativeCWA proteins was detected in the non-SIG staphylococcal speciesexamined. Results are summarised in FIG. 2. Of note, it cannot beexcluded at this point that DNA sequence variation in PCR primerannealing sites for spsP and spsQ, and weak homology (less thanapproximate 70%) for spsA to spsO among different strains haveinfluenced the results.

Expression of CWA Proteins on the S. pseudintermedius Bacterial CellSurface.

The in silico identification of 17 putative CWA proteins in S.pseudintermedius ED99 raises questions about the expression of theseproteins and their role in colonisation and disease. Surface proteomeanalysis of early-, mid-, and late exponential phase S. pseudintermediusED99 was performed in collaboration with the Moredun Research Institute,Penicuik, Scotland, UK, using liquid chromatography-electrosprayionisation-tandem mass spectrometry (LC-ESI-MS-MS). Six out of the 17putative CWA proteins predicted in the S. pseudintermedius ED99 genomewere detected on the bacterial surface, including SpsD, SpsK, SpsL,SpsN, SpsO, and SpsQ. The putative CWA proteins SpsL, SpsN, and SpsQwere identified in all three phases of growth; SpsK was lacking inearly-, SpsO in mid-, and SpsD in late exponential phase. The 11undetected CWA proteins might not have been expressed under theconditions tested, or the expression level might have been below thedetection threshold of the LC-ESI-MS-MS method used.

Cloning and Expression of SpsD, SpsL, and SpsO in L. lactis.

In order to examine the role of putative selected MSCRAMMs independentlyon the bacterial cell surface, the full-length spsD (3096 bp), spsL(2793 bp) and spsO (5538 bp) genes were cloned into L. lactis using theshuttle vector pOri23 (Que et al., 2000). Positive clones wereidentified by restriction digestion of purified pOri23 plasmids fromsingle colonies of transformed L. lactis cells (data not shown). ThepOri23 construct inserts were verified by DNA sequencing for spsL andspsD. For spsO, DNA sequence was generated for approximately 3000 bp ofthe total length of 5538 bp. A segment of the repeat regioncorresponding to ˜2500 bp could not be determined due to the existenceof identical tandem repeats which did not allow directed sequencing. Asa negative control for subsequent MSCRAMM characterisation studies, L.lactis was transformed with the empty vector pOri23, confirmed byrestriction digestion analysis. The predicted molecular weights were 115kDa for SpsD, 103 kDa for SpsL, and 198 kDa for SpsO.

L. lactis Expressing SpsD and SpsL Demonstrated Seroreactivity withCanine Sera from Pyoderma Cases.

The potential antibody response to SpsD, SpsL, and SpsO in vivo wasinvestigated by Western blot analysis employing canine sera fromstaphylococcal pyoderma cases. The pyoderma was clinically manifested atthe time of blood sampling and the dogs were also diagnosed with AD(Neuber et al., 2008). Cell wall-associated protein fractions of the L.lactis constructs and of S. pseudintermedius ED99 were subjected toSDS-PAGE, transferred to nitrocellulose membrane and incubated withpooled canine sera from three pyoderma cases as described in Materialsand Methods. An array of immunoreactive bands was detected for S.pseudintermedius ED99, ranging from 24 kDa to 102 kDa in molecularweight (FIG. 3). For L. lactis expressing SpsD and L. lactis expressingSpsL, multiple seroreactive bands in the range of 38 kDa to 225 kDa forSpsD, and 38 kDa and 52 kDa for SpsL were detected, which were absent inthe protein fractions of L. lactis carrying pOri23 alone (FIG. 3). Incontrast, L. lactis expressing SpsO did not demonstrate seroreactivitywith sera from dogs diagnosed with pyoderma (FIG. 3).

Adherence of L. lactis Constructs to Extracellular Matrix Proteins.

L. lactis expressing SpsO, SpsD, SpsL, and L. lactis carrying the vectorpOri23 alone were tested for their ability to adhere to human Fn, human,canine, feline, and bovine Fg, and to recombinant mouse CK10 in solidphase assays.

The Putative MSCRAMMs SpsD and SpsL Mediate Binding of L. lactis toFibronectin.

L. lactis expressing SpsD and SpsL demonstrated adherence to human Fn,whereas L. lactis expressing SpsO demonstrated increased binding to Fn,but also to BSA, indicative of a non-specific interaction (FIG. 4).

The Putative MSCRAMMs SpsD and SpsL Mediate Binding of L. lactis toFibrinogen, and SpsL Demonstrates Canine Host-Specificity.

L. lactis expressing SpsD strongly adhered to Fg from several animalsources (FIG. 5). In contrast, L. lactis expressing SpsL adhered tocanine and feline Fg only, and did not bind to human and bovine Fg (FIG.5), indicating a host-specific interaction. L. lactis expressing SpsOdid not bind to Fg from any source compared to L. lactis with the pOri23vector alone (FIG. 5).

The Putative MSCRAMM SpsD Mediates Binding of L. lactis to Cytokeratin10.

L. lactis expressing SpsD demonstrated strong adherence to CK10, whereasL. lactis expressing SpsO and SpsL did not show increased bindingcompared to L. lactis with the vector pOri23 alone (FIG. 6).

The Putative MSCRAMMs SpsD and SpsO, but not SpsL, Mediate Adherence ofL. lactis to Ex Vivo Canine Corneocytes.

L. lactis expressing SpsD, SpsL, and SpsO were tested for their abilityto adhere to ex vivo canine corneocytes in comparison to L. lactis withthe empty vector pOri23 and S. pseudintermedius ED99. L. lactis carryingthe empty vector pOri23 adhered poorly to canine corneocytes (FIG. 7).For S. pseudintermedius ED99, the mean percentage adherence to caninecorneocytes was 4.24% which was significantly different to L. lactiscarrying pOri23 alone (P=0.001) (FIG. 7). L. lactis expressing SpsD andL. lactis expressing SpsO adhered to ex vivo canine corneocytes (FIG.7). The increase in adherence was approaching significance for SpsD(P=0.050), and was significant for SpsO when expressed in L. lactiscompared to L. lactis carrying pOri23 alone (P=0.004). Binding of L.lactis expressing SpsL was not significantly different to L. lactiscarrying pOri23 alone (P=0.108), indicating that SpsL does not promoteadherence to canine corneocytes (FIG. 7).

Purified Recombinant Sps D, Sps L and Sps O Demonstrate Reactivity withCanine Convalescent Serum.

Reactivity of recombinant A domain from Sps D, Sps L and Sps O withcanine convalescent serum from pyoderma cases was examined by Westernaffinity blot analysis (FIG. 8). rSpsD, rSpsL and rSpsO all crossreactedwith IgG present in the canine serum (FIG. 8).

Pre-Incubation with Canine Convalescent Serum Inhibits SpsL-MediatedBinding to Fibrinogen.

The ability of the reactive antibody present in convalescent serum toinhibit SpsD and SpsL ligand binding was investigated using a modifiedsolid phase adherence assay. Prior to inoculation into fibrinogen coatedwells, PBS normalised cultures of L. lactis expressing SpsD and SpsLwere incubated for 2 h with doubling dilutions of convalescent serum at28° C. (FIG. 9). Convalescent serum inhibited binding of L. lactisexpressing SpsL, but not SpsD to canine fibrinogen, with completeinhibition at a final concentration of 2% v/v (FIG. 9).

Discussion

In summary, genome-wide analysis of S. pseudintermedius ED99 revealedthe presence of 17 genes encoding putative CWA proteins based on typicalMSCRAMM features. All MSCRAMM characteristics searched for wereidentified for SpsD, SpsL, and SpsO, including a signal sequence, anon-repeated A domain with two IgG-like folds, tandemly repeatedregions, and a C-terminal LPXTG-anchor motif. Interestingly, SpsD, SpsL,and SpsO belong to different groups based on Southern blot analysis,with SpsD being present in all SIG members, SpsL in S. pseudintermediusonly, and SpsO in only six of the S. pseudintermedius strainsinvestigated, and not in the other SIG species tested. Based on insilico analysis and in vitro expression data, SpsD, SpsL, and SpsO wereselected for functional characterisation.

All CWA proteins and in particular, SpsD, SpsL, and SpsO could beemployed in passive and active immunisation studies to test theirantigenic properties, either singular or in combination, in a similarfashion as proposed for S. aureus ClfA (Josefsson et al., 2001; Hall etal., 2003; Patti, 2004; Nanra et al., 2009). Further, a combinatoryvaccine of S. aureus surface proteins IsdA, iron-regulated surfacedeterminant protein B (IsdB), SdrD, and SdrE has proven to be highlyprotective in a mouse infection model (Stranger-Jones et al., 2006),demonstrating the promising potential of vaccine preparations containingmultiple staphylococcal CWA proteins.

In addition, MSCRAMMs with known ligands could be targets ofanti-staphylococcal drug development, e.g. by generating syntheticpeptides based on the interacting ECM proteins, which antagonise theMSCRAMM-host protein interaction, but do not interfere profoundly withphysiological processes in the host. An excellent example is provided byGanesh et al. (2008) who demonstrated that synthetic peptides, based onthe Fg-binding site for ClfA, hinder the ClfA interaction, but do notblock binding of the platelet integrin α_(IIb)β₃ to Fg. Recently,Stranger-Jones et al screened the genome of the human pathogen S. aureusfor all genes predicted to encode CWA proteins, and immunized mice witheach protein to determine their capacity to protect against lethal orinvasive infection (Stranger-Jones et al, 2006). Four of the proteinswere combined into a multiple protein vaccine which induced high levelsof protection against S. aureus invasive disease of mice. These datahave stimulated renewed optimism in a vaccine for the prevention ofhuman S. aureus infections. A similar approach could be used to designan effective vaccine for the prevention of S. pseudintermedius caninepyoderma.

Example 2

Staphylococcus pseudintermedius Surface Protein Vaccination Experiment.

S. pseudintermedius surface antigens were divided into 2 pools of 3 and4 antigens, respectively. Vaccine pool 1 contained antigens SpsC, IsaA,and SpsN and vaccine pool 2 contained SpsD A domain, N2, N3 subdomains,SpsL A domain (SEQ ID NO: 37), and SpsA.

Groups of 8 or 9 BalbC mice were vaccinated subcutaneously with pool 1or pool 2 or PBS, each with complete Freund's adjuvant, followed byadditional vaccinations at day 8 and day 23 with incomplete Freund'sadjuvant. On day 32, mice were challenged through a subcutaneous routewith 10⁷ cfu S. pseudintermedius ED99. Mice were then examined forabscess formation, and weight loss.

Mice vaccinated with pool 2 (comprising the protein having amino acidsequence provided in SEQ ID NO: 37) had significantly reduced lesionsize (˜50% reduction), and significantly reduced weight loss (˜50%)compared to PBS control mock vaccinated animals.

REFERENCES

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TABLE 1 Sequence homology of the 17 predicted cell-wall-anchoredproteins against known proteins in the public domain. Putative CWAIdentity Similarity protein Best Hit (BLAST) (%) (%) SpsA LPXTGcell-wall surface anchor family protein of S. aureus COL 31.2 56.9 SpsBRodA, a rod shape determining protein of S. epidermidis ATCC 12228 69.787.8 SpsC bifunctional autolysin precursor of S. epidermidis ATCC 1222850.7 65.9 SpsD Fnbp protein homolog of S. aureus Mu50 40.7 59.1 SpsEFibrinogen binding protein of S. epidermidis ATCC 12228 78.6 90.1 SpsFhypothetical protein, similar to the putative cell-surface adhesin SdrFof S. haemolyticus JCSC1435 52.8 69.3 SpsG hypothetical protein,cell-wall surface anchor family of Streptococcus pneumoniae D39 47.763.6 SpsH Sdr-repeat family protein SdrH, S. aureus USA300 36.0 53.1SpsI serine-aspartate rich, fibrinogen-binding, bonesialoprotein-binding protein S. epidermidis ATCC 12228 37.3 55.5 SpsJprecursor of a serine-rich adhesin for platelets of S. haemolyticusJCSC143S 52.2 61.2 SpsK IgG-binding protein of S. aureus COL 50.4 71.1SpsL Fnbp protein homolog of S. aureus Mu50 33.4 51.7 SpsM hypotheticalprotein, similar to the putative cell-surface adhesin SdrF, S.haemolyticus JCSC1435 44.4 61.7 SpsN probable exported protein of S.aureus RF122 38.0 60.0 SpsO serine-aspartate repeat-containing protein Cprecursor of Staphylococcus warneri L37603 50.0 68 SpsP LPXTG-motif cellwall anchor domain of S. aureus JH9 60.6 74.3 SpsQ IgG-binding protein Aprecursor of S. aureus MRSA252 57.0 71.7

TABLE 2 Main characteristics of the predicted CWA proteins SpsD, SpsL,and SpsO of S. pseudintermedius ED99. TYTFTDYVD- Putative latchingRepeat Copy Amino MW Signal LPXTG Ig-like fold^(b) like motif sequenceregion number acids (kDa)^(a) peptide motif (position) (position)^(b)(position)^(b) (position) repeats SpsD 1031 115 36 aa LPDTG 167-320 aaRYRFMDYVN NNASGEG 867-959 aa 5 322-519 aa (267-275 aa) (491-497 aa) SpsL930 103 38 aa LPKTG 220-363 aa VYTFKDYVN NSASGSG 543-818 aa 7 364-531 aa(298-306 aa) (502-508 aa) SpsO 1846 198 44 aa LPNTG 339-492 aa TYTFTDYVDDKSTALG 661-1800 aa  96  487-659 aa (424-432 aa) (635-641 aa)   97-216aa^(c)  4^(c) aa = amino acids; ^(a)MW = predicted approximate molecularweight in kDa (kilo dalton); ^(b)within the A domain; ^(c)N-terminalrepeats

1. A Staphylococcus pseudintermedius protein or nucleic acid comprisinga sequence at least 65% homologous or identical to SEQ ID NOS: 1-38 orfragments, portions, mutants, derivatives and/or homologoues/orthologuesthereof.
 2. The Staphylococcus pseudintermedius protein or nucleic acidof claim 1, comprising a sequence at least 65% homologous or identicalto (i) the nucleic acid of SEQ ID NO: 5 or a fragment thereof or (ii)the amino acid sequence of SEQ ID NO: 6 or an antigenic fragmentthereof, for use in raising an immune response in a subject.
 3. TheStaphylococcus pseudintermedius protein of claim 2, comprising anantigenic fragment of the amino acid sequence of SEQ ID NO: 6, whereinsaid fragment comprises SEQ ID NO:
 37. 4. The Staphylococcuspseudintermedius nucleic acid of claim 2, comprising a fragment of thenucleic acid, wherein said fragment comprises SEQ ID NO:
 38. 5. TheStaphylococcus pseudintermedius protein of claim 1, wherein the proteinis a cell-wall anchored (CWA) or microbial surface componentsrecognising adhesive matrix molecule (MSCRAMM).
 6. The Staphylococcuspseudintermedius protein of claim 1, comprising a replicable expressionvector and nucleic acid.
 7. A host cell transformed with the nucleicacid of claim
 6. 8. The Staphylococcus pseudintermedius protein of claim1, comprising an amino acid sequence having at least 80% identity to SEQID NO:
 5. 9. A Staphylococcus pseudintermedius protein comprising anamino acid sequence having at least 80% identity to SEQ ID NO:
 37. 10.The Staphylococcus pseudintermedius protein of claim 9, comprising anamino acid sequence having at least 90% identity to SEQ ID NO:
 37. 11. Amethod of raising an immune response to Staphylococcus pseudintermediusin a canine, said method comprising immunising said canine with, oradministering said canine a Staphylococcus pseudintermedius proteinaccording to claim
 1. 12. An immunogenic composition comprising theprotein of claim 1 and a pharmaceutically acceptable carrier.
 13. Theimmunogenic composition of claim 12, further comprising one or moreadjuvant(s) and/or antigens for use in treating or preventing otherdiseases and/or conditions.
 14. A method of treating or preventing aStaphylococcus pseudintermedius infection or disease in a canine, saidmethod comprising administering to the canine the immunogeniccomposition of claim
 12. 15. A method of treating or preventing caninepyoderma comprising administering to a dog the immunogenic compositionof claim
 12. 16. A process for the recombinant production of aStaphylococcus pseudintermedius protein of claim 1, said processcomprising the steps of: (a) transforming a host cell with the nucleicacid of claim 1; (b) culturing the cells obtained in (a) underconditions in which expression of a peptide/protein encoded by thenucleic acid occurs; and (c) isolating the expressed peptide/proteinfrom the cell culture or/and a culture supernatant derived therefrom.17. An antibody that selectively and/or specifically binds to theStaphylococcus pseudintermedius protein of claim
 1. 18. An antibody thatselectively and/or specifically binds to the Staphylococcuspseudintermedius protein of claim
 9. 19. A method of diagnosing an S.pseudintermedius infection, said method comprising the steps of taking asample from a canine, identifying in the sample a level of a protein ornucleic acid of claim 1, wherein the subject is diagnosed with S.pseudintermedius infection by identification of the protein, peptide ornucleic in the sample.
 20. A kit for diagnosing, detecting and/orevaluating possible S. pseudintermedius infections, diseases and/orconditions, said kit comprising one or more components selected from thegroup consisting of: (i) a substrate having the Staphylococcuspseudintermedius protein of claim 1 bound thereto; (ii) antibodies whichexhibit specificity and/or selectivity for the protein; (iii) andinstructions for diagnosing, detecting and/or evaluating possible S.pseudintermedius infections, diseases and/or conditions.